Medetomidine analogs as α2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with α2-adrenoceptors involving a 'methyl pocket'

Article abstract of DOI:10.1021/jm960642q

The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the α₂- adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent α₂-adrenoceptor binding ligand among these 4-substituted imidazoles, and its α₂-adrenoceptor selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize α₂-adrenoceptor binding data of the imidazole analogs in terms of ligand-receptor interactions. The structure-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the α₂-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the α-methyl group of (-)-α-methylnorepinephrine and fit into the proposed 'methyl pocket' of the α₂-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.

Full text of DOI:10.1021/jm960642q

3014
J . Med. Chem. 1997, 40, 3014-3024
Med etom id in e An a logs a s r2-Ad r en er gic Liga n d s. 3. Syn th esis a n d Biologica l
Eva lu a tion of a New Ser ies of Med etom id in e An a logs a n d Th eir P oten tia l
Bin d in g In ter a ction s w ith r2-Ad r en ocep tor s In volvin g a “Meth yl P ock et”
Xiaoyan Zhang,† J oseph E. De Los Angeles, Mei-Ying He, J ames T. Dalton, Gamal Shams,‡ Longping Lei,‡
Popat N. Patil,‡ Dennis R. Feller,§ Duane D. Miller,* and Fu-Lian Hsu|
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, 847 Monroe Avenue,
Room 327, Memphis, Tennessee 38163
Received September 10, 1996X
The synthesis and the biological evaluation of a new series of medetomidine analogs are
reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct
influence on the R2-adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent
R2-adrenoceptor binding ligand among these 4-substituted imidazoles, and its R2-adrenoceptor
selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and
receptor modeling were combined to rationalize R2-adrenoceptor binding data of the imidazole
analogs in terms of ligand-receptor interactions. The structure-activity relationships that
were apparent from this and previous studies were qualitatively rationalized by the binding
site models of the R2-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl
analog 2a was superimposable with the R-methyl group of (-)-R-methylnorepinephrine and
fit into the proposed “methyl pocket” of the R2-adrenoceptor defined by the residues Leu110,
Leu169, Phe391, and Thr395.
In tr od u ction
Medetomidine (1) is the prototype of a class of
R-adrenoceptor agents.1 We previously described the
synthesis, biological evaluation, and computer modeling
studies of the 4-substituted imidazoles as R-adrenocep-
tor agents.2,3 Naphthyl analog 2a exhibited equal
potency and higher selectivity at R2-adrenoceptors than
medetomidine. Conformationally restricted analog 3a
of the naphthyl series retained high binding affinity but
low selectivity at R2-adrenoceptors. In a subsequent
study, we found that an unsubstituted tetralin analog
of medetomidine 4a showed moderate binding affinity
at R2-adrenoceptors,4 whereas the 5-methoxytetralin
analog 4b was very potent on R2-adrenoceptors.5 In this
paper, we have further explored the structure-activity
relationships of a tetralin series (4c-g) by placing
various substituents at the different positions of the
phenyl ring. The synthetic intermediates of the tetralin
series, 3,4-dihydronaphthalene analogs 5c-g, were also
examined for their R-adrenoceptor binding affinities.
These two series are conformationally restricted analogs
of medetomidine, as the connection of the benzylic meth-
yl substituent with the o-methyl group on the phenyl
ring decreases the rotational flexibility of C1-CR bond
in medetomidine. We also synthesized a 4-methylindan
analog 6 as a comparison with the 5-methyltetralin
During the course of our synthetic research, we
conducted molecular modeling studies on the medeto-
midine-like analogs and found a common binding mode
of the phenethylamines and the imidazoles with R2-
adrenoceptors by superimposition of the imidazole
analogs with (-)-R-methylnorepinephrine (R-MeNE).3
Recently acquired knowledge regarding the amino acid
sequence of the R2-adrenoceptor and the availability of
a high-resolution three-dimensional structure of bac-
teriorhodopsin makes it attractive to construct an R2-
analog 4c.
† Present address: Laboratory of Medicinal Chemistry, Bldg. 8, Rm.
B1-21, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, MD 20892.
‡ Division of Pharmacology, College of Pharmacy, The Ohio State
University, Columbus, Ohio 43210.
§ Department of Pharmacology, School of Pharmacy, University of
Mississippi, University, MS 38677.
| U.S. Army Edgewood Research Development and Engineering
Center, Aberdeen P. G., MD 21010-5423.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0022-2623(96)00642-5 CCC: $14.00 © 1997 American Chemical Society

Medetomidine Analogs as R2-Adrenergic Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3015
was carried out by using TiCl4 as a Lewis acid. The
synthesis of target compound 6 was accomplished
successfully from alcohol 14 by using Me3SiCl-NaI-
CH3CN.9
Biologica l Resu lts
F igu r e 1. Retrosynthesis of 4-substituted imidazoles.
The R1- and R2-adrenoceptor binding affinities of the
newly synthesized 4-substituted imidazoles were deter-
mined using membrane fractions of rat brain, as sum-
marized in Table 1. The substitution pattern at the
phenyl ring of tetralin analogs had a distinct influence
on the R2-adrenoceptor binding affinities. All 5-substi-
tuted tetralin analogs (4b-e) were about equipotent,
displaying R2-adrenoceptor binding affinities ranging
from 63-103 nM. Compounds lacking the 5-substituent
(4f-g) were less potent in binding to R2-adrenoceptors.
We previously reported that the unsubstituted tetralin
analog 4a exhibited moderate activity at the R2-adreno-
ceptor.4 Taken together, these findings suggest that the
presence of a substituent at the 5-position of tetralin
analogs is critical to obtain optimal R2-adrenoceptor
binding. Based on Ki values, the rank order of R1-
adrenoceptor affinities for the tetralin analogs is as
follows: 5-OH (4d ) ≈ 5,7-diCH3 (4e) > 5-CH3 (4c) ≈
6-OCH3 (4f) > 5-OCH3 (4b) . 7-OCH3 (4g). In general,
compounds in this series did not exhibit high selectivity
for R2- vs R1-adrenoceptors. Although 3,4-dihydronaph-
thalene analogs 5b-g were generally less potent than
their corresponding tetralin analogs 4b-g, the 5-meth-
yl-substituted analog 5c was 3-fold more potent at the
R2-adrenoceptor and showed much higher selectivity at
the R2-adrenoceptor than the corresponding 5-methyl
tetralin analog 4c. Similarly, the 5,7-dimethyl analog
5e also exhibited higher selectivity for R2- vs R1-
adrenoceptors than its corresponding tetralin analog 4e.
4-Methylindan analog 6 was the most potent R2-adreno-
ceptor binding ligand among these 4-substituted imi-
dazoles, and its R2-adrenoceptor selectivity was greater
than the 5-methyltetralin analog 4c.
Sch em e 1a
a
(a) Triphenyl(2-carboxyethyl)phosphonium chloride, NaH,
THF/DMSO (1:1), 0 °C f rt, (b) H2 (30 psi), Pd/C (10%), EtOH; (c)
(i) PCl5, benzene, (ii) SnCl4. (d) PhCH2Br, K2CO3, CHCl3/CH3OH,
reflux.
adrenoceptor model. In fact, a number of such models
have been reported.6,7 Herein we used an approach in
which ligand-pharmacophore and receptor modeling
were combined to rationalize R2-adrenoceptor binding
data of the imidazole analogs in terms of ligand-
receptor interactions. The biological data reported in
this paper and in the preceding papers2,3 appear to
accommodate the deduced R2-adrenoceptor binding site
models in a qualitative sense. Consequently, this
proposed model may be useful in the design of novel R2-
adrenoceptor drugs.
Ch em istr y
Racemic analogs 4b-g and analogs 5b-g were syn-
thesized by a straightforward method utilizing direct
introduction of an intact imidazole, as we have previ-
ously reported.3 The final compounds were derived from
the appropriately substituted carbonyl precursors, 9b-
g, as illustrated in Figure 1. The preparation of the
non-commercially available tetralones (9c and 9d ) is
depicted in Scheme 1. Treatment of 2-methylbenzal-
dehyde with triphenyl(2-carboxyethyl)phosphonium chlo-
ride provided a mixture of alkenes 7 with both cis and
trans configurations. Without further isolation, this
mixture was hydrogenated to the saturated carboxylic
acid 8, which was then cyclized to the corresponding
1-tetralone 9c. The synthesis of 5-hydroxytetralin
analog was initiated from 5-hydroxy-1-tetralone, in
which the hydroxy group was protected as a benzyl
ether (9d ) before subjecting it to the Grignard reaction.
Ketones 9b-g were converted to the corresponding
alcohols 10b-g using Turner’s approach (Scheme 2).8
Deprotection of the imidazole ring afforded a series of
3,4-dihydronaphthalene analogs (5b-g), which were
individually hydrogenated to give a series of 1,2,3,4-
tetrahydronaphthalene analogs (4b-g).
Molecu la r Mod elin g
R2-Adrenoceptors (R2A-D) belong to a family of G-
protein-coupled receptors (GPCR) that transmit infor-
mation into the interior of cells through coupling to
guanine nucleotide regulatory proteins (G-protein).10
The R2-adrenoceptors have been cloned and proposed
to consist of seven transmembrane-spanning domains
that are connected by three extracellular and three
intracellular loops, with the amino terminus being
extracellular and the carboxy terminus intracellular.
The 3D structure of the transmembrane-spanning R-he-
lices of the R2-adrenoceptor might resemble the folding
of bacteriorhodopsin, a membrane protein whose 3D
structure has recently been obtained by cryomicros-
copy.11
The R2-adrenoceptor-ligand interactions have been
studied by site-directed mutagenesis.12,13 Several con-
clusions can be drawn from these studies. (1) The
carboxy group of Asp113 in transmembrane domain III
(TM3) interacts with the protonated amino group of
phenethylamines, such as norepinephrine. (2) The m-
and p-hydroxy groups of phenethylamines are postu-
lated to form hydrogen bonds to Cys201 and Ser204,
respectively, which are located in the fifth transmem-
brane spanning helix (TM5). (3) The hydroxy group of
4-Methyl-1-indanone (13, Scheme 3) was prepared
following a similar route for the synthesis of perinaph-
thanone, as we reported earlier.3 Difficulties were
encountered in the cyclization step using SnCl4 or
AlCl3 as the Friedel-Crafts catalyst. However, this step

3016 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Zhang et al.
Sch em e 2a
a
(a) 4-Iodo-N-tritylimidazole, EtMgBr, CH2Cl2; (b) TFA/H2O (60%); (c) maleic acid, CH3OH; (d) H2 (30 psi), Pd/C (10%), EtOH; (e)
maleic acid, CH3OH.
Sch em e 3a
a
(a) CH2(CO2C2H5)2, NaOC2H5, HOC2H5, reflux; (b) KOH/H2O, reflux, (c) 160 °C; (d) (i) SOCl2, (ii) TiCl4, CH2Cl2; (e) 4-iodo-N-
tritylimidazole, EtMgBr, CH2Cl2; (f) TMSCl-NaI-CH3CN, CH2Cl2; (g) maleic acid, CH3OH.
Ser90 in TM2 could be the potential binding site for the
â-hydroxy group of phenethylamines.13 In our studies,
the model of the human R2-adrenoceptor was con-
structed using SYBYL and a strategy similar to that
previously described by Hibert et al.6 The template
molecule of the phenethylamine, R-MeNE, and the more
active S-isomers of medetomidine analogs were docked
into the model individually. When trying to locate the
binding site of R-MeNE with the R2-adrenoceptor, we
considered the interactions between the ligand and the
important amino acid residues discussed above.
the ideal position in the recognition site to form a
hydrogen bond with the â-hydroxy group of R-MeNE.
Such an interaction was also suggested in the Trumpp-
Kallmeyer’s model.7 The R-methyl group of R-MeNE
was surrounded by the side chain of Leu110 (in TM3),
Leu169 (in TM4), Phe391 and Thr395 (in TM6). This
lipophilic cavity (the “methyl pocket”) formed by the
above four amino acid residues could be the additional
recognition binding site at the R2-adrenoceptor for the
R-methyl group of R-methylphenethylamines, as pro-
posed in 1970s by Ruffolo et al.14
In the binding site model for the R-MeNE R2-adreno-
ceptor complex (Figure 2), the protonated nitrogen of
the ligand interacted with Aps113 in TM3 through a
reinforced ionic bond. Hydrogen bonds were formed
from the meta- and para- phenolic hydrogens of the
ligand to Cys201 and Ser204 (in TM5), respectively.
Aromatic edge-to-face interactions occurred between the
aromatic moiety of the ligand and Phe205 (in TM4) and
Phe391 (in TM6). The â-hydroxy group of Ser90 in
TM2, a potential binding site for the â-hydroxy group
of phenethylamines as indicated in the site-directed
mutagenesis experiments,13 was too far removed from
the binding pocket in our proposed model. However,
we found another Ser residue, Ser165 in TM4, occupied
In a recent meeting on R2-adrenoceptors, Heible and
co-workers reported that Ser165 may not be involved
in the hydrogen bonding interactions with the â-hy-
droxyl group of catecholamines based on their site-
directed mutagenesis studies.15 Instead, their data
indicated that Ser90 (TM2) and/or Ser419 (TM7) are the
likely sites of hydrogen bonding interactions for the
â-hydroxyl group. Mutation of either Ser90 or Ser419
to Ala resulted in 50-70 fold reduction in Ki values for
(-)-epinephrine and (-)-norepinephrine but little if any
change in the binding affinity of the less active (+)
enantiomers and dopamine which lacks the â-hydroxyl
group. These results do not appear to be consistent with
our bacteriorhodopsin derived model of the R2-adreno-

Medetomidine Analogs as R2-Adrenergic Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3017
Ta ble 1. R1- and R2-Adrenergic Binding Affinities of Conformationally Restricted Analogs of Medetomidine in Membrane
Preparations of Rat Brain
Ki (nM)a
R2-selectivity
compound
R
R1
R2
ratiob
medetomidine
1110 ( 36
243 ( 30
25 ( 13
98 ( 6
44.4
2.48
2.10
2.01
32.0
2.01
3.09
1.27
12.8
1.17
2.81
8.81
9.03
8.29
4b
5b
4c
5c
4d
5d
4e
5e
4f
5f
4g
5g
6
5-OCH3
5-OCH3
5-CH3
5-CH3
5-OH
2970 ( 75
191 ( 20
1420 ( 812
95 ( 12
992 ( 21
126 ( 16
31 ( 11
63 ( 10
5-OBn
8250 ( 1414
131 ( 49
2670 ( 637
103 ( 34
232 ( 67
169 ( 26
580 ( 74
201 ( 98
1570 ( 159
8.8 ( 1.5
5,7-diCH3
5,7-diCH3
6-OCH3
6-OCH3
7-OCH3
7-OCH3
4-CH3
2960 ( 603
198 ( 80
1630 ( 440
1770 ( 494
14200 ( 4378
73 ( 28
a
Rat brain membrane preparations were incubated with 0.1 nM of [3H]prazosin and 0.2 nM of [3H]rauwolscine for R1- and
R2-adrenoceptors, respectively. Phentolamine (10 µM) was used to determine the fraction of nonspecific binding in both assays. Ki values
were determined using the equation as follows: Ki (nM) ) IC50 (1 + [L]/Kd), where IC50 ) concentration (nM) of analog which reduces
binding by 50%; [L] ) concentration of radioligand; and Kd ) equilibrium dissociation constant of the radioligand. Values are average (
b
standard deviation (n ) 3-9). R2-Selectivity ratio ) Ki (R1)/Ki (R2).
ceptor. In our hypothetical model, the ligand binding
site is formed by TM3, TM4, TM5, and TM6, and inter-
action of the â-hydroxyl group with either Ser90 or
Ser419 would preclude important interactions with
Asp113 (TM3), Cys201 (TM5), and Ser204 (TM5). Thus,
if Ser90 and/or Ser419 do in fact form a hydrogen bond
with the â-hydroxyl group of catecholamines, these re-
cent mutational studies appear to be incompatible with
our receptor model. A receptor model that can account
for these recent and previous mutation studies would
require a helical arrangement different from our model
and bacteriorhodopsin. However, site-directed muta-
genesis and chimeric receptor studies provide strong evi-
dence that the transmembrane domains of G-protein-
coupled receptors such as R2- and â2-adrenoceptors have
a helical arrangement similar to bacteriorhodopsin.16 In
addition, the length of the extracellular and intracel-
lular loops would seem to prevent helical arrangements
that can accommodate these new findings.15 Further-
more, one cannot dismiss the possibility of multiple
binding modes or mutation-induced perturbations of the
receptor binding site that may account for the observed
binding of catecholamines to the Ala90 and Ala419 R2-
adrenoceptor mutants. The lack of change in catechola-
mine binding to Ala165 mutants is not unusual as some
mutations of important serine residues in various
GPCRs may have little if any effect on binding affinities
but have significant effect on G-protein coupling or
functional activity.12,17-19 Thus, the hypothetical 3D
model of the R2-adrenoceptor presented here may be
valid and can provide at least a qualitative assessment
of ligand binding interactions.
vs R1-adrenoceptors. We proposed that the benzylic
methyl group of medetomidine interacts with the same
site as the R-methyl group of R-MeNE.3 Since the
S-isomer of medetomidine and (S)-2a is the active
isomer for R2-adrenoceptors, we assumed that the
S-isomer of other imidazole analogs is the more potent
optical isomer for R2-adrenoceptors if the racemate is
active. As illustrated in Figure 3, one of the attractive
features of the model reported herein is that it allowed
for superimposition of the pharmacophoric elements (the
nitrogen atom, the methyl group, and the aromatic
moiety) of the two molecules without a significant
change in the docking energies (-46 cal/mol for R-MeNE
and -50 cal/mol for (S)-medetomidine). Interestingly,
the other nitrogen of the imidazole ring, N1, was
postulated to form a hydrogen bond with the back-
bone carbonyl of Leu110 (TM3), instead of Ser165 in
TM4.
Effects of th e Ben zylic Su bstitu en ts in Na p h th yl
Der iva tives. The binding site model of the R2-adreno-
ceptor provided insight into the molecular basis for the
observed binding differences of (S)-2a and 2b at the R2-
adrenoceptor.3 In the docking model of R-MeNE, (S)-
medetomidine and (S)-2a (Figure 4a-c), the methyl
group (illustrated by van de Waals surface) fit nicely
into the “methyl pocket” as described above. However,
the ethylene side chain of 2b was obviously too large to
fit into the “methyl pocket” (Figure 4d). Such a binding
pattern was also observed when molecule 3a and 3b
were docked into the R2-adrenoceptor model, respec-
tively. These observations appear to rationalize the fact
that medetomidine, 2a , and 3a exhibited high affinity
for the R2-adrenoceptors, while 2b and 3b did not.
In the preceding paper, we reported that medetomi-
dine has much higher binding affinity at the R2-
adrenoceptor than R-MeNE with equal selectivity at R2-
Effects of th e P h en yl Su bstitu en ts in Tetr a lin
Ser ies. In the present series, substituents on the

3018 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Zhang et al.
F igu r e 2. View of the seven transmembrane regions of the R2-adrenoceptor and R-MeNE complex. The seven helices are indicated
by the cR-carbon trace. Only the residues around the binding site are displayed. Serine residues are yellow. Cys201 is green. Asp
113 is orange and the hydrophobic residues are red.
phenyl ring of the tetralin series have an important
influence on R2-adrenoceptor binding affinity. Super-
imposition of R-MeNE and the 5-methoxytetralin analog
4b resulted in the overlap of the m-OH of R-MeNE and
the 5-OCH3 group of 4b, suggesting that the 5-OCH3 of
4b may interact with Cys201 in TM5. Interestingly,
when 4b was docked into the R2-adrenoceptor model,
the distance of oxygen atom of 5-OCH3 in 4b to the
oxygen atom of Ser165 and the sulfur atom of Cys201
was 3.6 and 3.4 Å, respectively. When 5-OH analog 4d
was docked into the R2-adrenoceptor model, the 5-OH
group formed a hydrogen bond with Ser165 in TM4,
instead of with Cys201. The docking energies of 4b and
4d in R2-model were -42 and -34 cal/mol, respectively.
Moving the methoxy to the sixth or seventh positions
(analogs 4f,g) resulted in an increase in the docking
energy to 453 and 128 cal/mol, respectively, indicating
less favorable interactions between 4f or 4g and the R2-
adrenoceptor. A schematic representation of the inter-
action of 4d with the binding site of the R2-adrenoceptor
is presented in Figure 5. The experimental evidence
and observations from the model suggested that the
cavity surrounded by Ser165 (in TM4) and Cys201 (in
TM5) was important to obtain high R2-adrenoceptor
binding affinity. It also provided a rationale for the
design of affinity labeling ligands based on the tetralin
structure. In addition, the benzylic bridge formed
between the C1 and the C2 of the 5-substituted tetralin
analogs or the indan analog 6 fit perfectly into the
“methyl pocket”.
Con clu sion s
Remarkably, the R2-adrenoceptor binding site model
accommodates the binding data of these medetomidine

Medetomidine Analogs as R2-Adrenergic Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3019
F igu r e 3. Stereo representation of the superimposition of R-MeNE (pink) and medetomidine (blue) in the binding site of R2-
adrenoceptor model.
solution, and extracted with Et2O (2 × 100 mL). The combined
ether extracts were washed with water (5 × 200 mL), dried
over MgSO4, and evaporated to yield a mixture of trans- and
cis-alkene isomers (7) in a 52% yield. This mixture (1.80 g,
10.2 mmol) was reduced by catalytic hydrogenation with
10% Pd/C (0.20 g) as a catalyst in absolute EtOH (100 mL) to
afford 1.71 g (94%) of acid 8 as a white fluffy solid: mp 57-58
analogs. In fact, the structure-activity relationships
of medetomidine analogs at the R2-adrenoceptor de-
scribed herein and the preceding papers2,3 can be
partially rationalized by the R2-adrenoceptor model. The
presence of the “methyl pocket” and the cavity sur-
rounded by Ser165 (in TM4) and Cys201 (in TM5) in
the binding site model are particularly interesting,
because these structural features of the R2-adrenoceptor
have been predicted on the basis of ligand-pharma-
cophore modeling and, thus, are supported by a wealth
of experimental evidence. Thus, it may be possible to
use the R2-adrenoceptor binding site model in the design
of affinity labeling ligands for the R2-adrenoceptors.
1
°C (lit.20 52-57 °C); H NMR (300 MHz, CDCl3) δ 1.90-1.98
(m, 2H, CH2), 2.31 (s, 3H, CH3), 2.41-2.46 (m, 2H, CH2CO),
2.64-2.69 (m, 2H, ArCH2), 7.11-7.14 (m, 4H, Ar-H); IR (KBr)
1718 cm-1; MS m/ e calcd for C11H14O2: 178, found 178. Anal.
(C11H14O2): C, H.
5-Meth yl-1-tetr a lon e (9c). 4-(2-Methylphenyl)butanoic
acid (8, 0.54 g, 3 mmol) was mixed with PCl5 (0.75 g, 3.6 mmol)
in dry benzene (5 mL). After stirring for 1 h, SnCl4 (0.6 mL,
5.1 mmol) was added dropwise at 0 °C. The mixture was
maintained at 0 °C for further 15 min and then quenched with
aqueous HCl solution (10%). The benzene layer was washed
successively with dilute acid, water, dilute alkali, water, and
brine. The organic solution was dried over MgSO4 and
concentrated. The crude product was recrystallized in hexane
to afford 0.44 g (92%) of 9c as white crystals: mp 49-50 °C
(lit.21 48-50 °C); 1H NMR (300 MHz, CDCl3) δ 2.13-2.21 (m,
2H, CH2), 2.32 (s, 3H, CH3), 2.62-2.66 (m, 2H, CH2CO), 2.86
(t, J ) 6.08 Hz, 2H, ArCH2), 7.19-7.26 (m, 1H, ArH), 7.35 (d,
J ) 7.42 Hz, 1H, ArH), 7.93 (d, J ) 7.76 Hz, 1H, ArH); IR
(KBr) 1673 cm-1; MS m/ e calcd for C11H12O: 160, found 160.
Anal. (C11H12O2): C, H.
4-[1-(1-Hydr oxy-5-m eth yl-1,2,3,4-tetr ah ydr on aph th yl)]-
N-(tr ip h en ylm eth yl)im id a zole (10c). A 3.0 M solution of
EtMgBr (1.5 mL, 4.5 mmol) in Et2O was added to a 0.25 M
solution of 4-iodo-N-(triphenylmethyl)imidazole22 (1.89 g, 4.3
mmol) in dry CH2Cl2 at ambient temperature. After 1 h, a
solution of 5-methyl-1-tetralone (9c, 0.46 g, 2.9 mmol) in 2 mL
of dry CH2Cl2 was added and stirring was continued overnight.
Saturated NH4Cl solution was added to quench the reaction.
The aqueous phase was extracted with an equal amount of
CH2Cl2 (2×). The combined organic extracts were washed with
brine, dried over MgSO4, and concentrated. The crude product
was crystallized in CH2Cl2/hexane to yield 1.01 g (75%) of the
title compound as a white solid: mp 122-123 °C; 1H NMR (300
MHz, CDCl3) δ 1.72-1.82 (m, 1H), 2.04-2.12 (m, 2H, CH2),
2.19 (s, 3H, CH3), 2.30-2.34 (m, 1H), 2.59-2.61 (m, 1H), 2.66-
2.68 (m, 1H), 3.18 (bs, 1H, OH), 6.46 (d, J ) 1.47 Hz, 1H, Im-
H), 6.99-7.02 (m, 2H), 7.08-7.14 (m, 7H), 7.28-7.34 (m, 9H),
7.37 (d, J ) 1.46 Hz, 1H, Im-H); IR (KBr) 3368, 1493, 1446
cm-1; MS m/ e calcd for C33H30N2O: 471, found 471. Anal.
(C33H30N2O‚1/2H2O‚CH2Cl2): C, H, N.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Thomas-
Hoover capillary melting point apparatus and are uncorrected.
NMR (1H and 13C) spectra were obtained on Bruker 300
spectrometer, and chemical shift values were reported as
parts per million (δ) relative to tetramethylsilane (TMS) as
an internal reference. IR spectra were obtained on Sys-
tem 2000-FTIR. Elemental analyses were performed by
Atlantic Microlab, Inc., and the obtained analytical results
were within (0.4% of the theoretical values. Routine thin-
layer chromatography (TLC) was performed on silica gel
UNIPLATE (250 µm, 2.5 × 10 cm; Analtech Inc. Newark, DE).
Flash chromatography was performed on silica gel (Merck,
Grade 9385, 230-400 mesh, 60 Å). Acetonitrile (CH3CN),
benzene, ethyl ether (Et2O), and methylene chloride (CH2Cl2)
were dried by distillation from CaH2. Tetrahydrofuran (THF)
was dried by distillation from sodium metal with benzophe-
none as an indicator. Unless specifically indicated otherwise
amine maleate salts were obtained and purified by the
dropwise addition of a molar equivalent solution of maleic acid
in anhydrous Et2O to a solution of the amine in absolute
methanol.
4-(2-Meth ylp h en yl)bu ta n oic Acid (8). To a solution of
2-methylbenzaldehyde (2 mL, 17.3 mmol) and triphenyl(2-
carboxyethyl)phosphonium chloride (6.60 g, 17.8 mmol) in a
1:1 mixture of dry THF/DMSO (50 mL) was added dry sodium
hydride powder (95%, 0.90 g, 35.6 mmol) in one portion at 0
°C under an atmosphere of argon. The resulting suspension
was allowed to stir overnight at room temperature. After
cooling to 0 °C, the dark-red mixture was diluted with 100
mL of water. The aqueous portion was washed with Et2O (3
× 100 mL), acidified to pH 1-2 with concentrated HCl

3020 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Zhang et al.

Medetomidine Analogs as R2-Adrenergic Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3021
F igu r e 5. Stereo representation of the interaction of 4d and the binding site of R2-adrenoceptor model.
4-(3,4-D ih y d r o -5-m e t h y l-1-n a p h t h y l)-1H -im id a zo -
liu m Ma lea te (5c). A solution of 10c (0.56 g, 1.2 mmol) in
10 mL of TFA aqueous solution (60%) was stirred overnight.
The solvents were evaporated, and the residue was partitioned
between 15 mL of CH2Cl2 and 15 mL of HCl solution (10%).
The organic portion was washed with HCl solution (10%, 3 ×
15 mL). The combined acidic solutions were made basic (pH
∼10) and then extracted with CH2Cl2 (4 × 75 mL). The
organics were dried over Na2SO4 and concentrated to yield 0.20
g (79%) of 5c as a free base, which was converted immedi-
ately to the maleate to afford the title compound as white
crystals: mp 149-150 °C; 1H NMR (300 MHz, CD3OD) δ 2.32
(s, 3H, CH3), 2.39-2.46 (m, 2H, CH2), 2.81 (t, J ) 7.79 Hz,
2H, Ar-CH2), 6.24 (s, 2H, HCdCH), 6.45 (t, J ) 4.77 Hz, 1H,
HCdC), 6.89 (d, J ) 7.56 Hz, 1H), 7.06-7.14 (m, 2H), 7.53 (s,
1H, Im-H), 8.82 (d, J ) 1.04 Hz, 1H, Im-H); 13C NMR (300
MHz, CD3OD) δ 19.69 (CH3), 23.95 (CH2), 24.20 (CH2), 170.71
(CdO); IR (KBr) 3448, 1572, 1455 cm-1; MS (chemical ioniza-
tion-NH3) m/ e calcd for C14H14N2 (MH+): 211, found 211.
Anal. (C18H18N2O4): C, H, N.
7.15 (m, 6H, Tr-H), 7.30-7.35 (m, 9H, Tr-H), 7.38 (d, J ) 1.45
Hz, 1H, Im-H); IR (KBr) 3233, 1492, 1445 cm-1; MS m/ e calcd
for C34H32N2O: 484, found 484. Anal. (C34H32N2O‚3/4CH2-
Cl2): C, H, N.
4-(3,4-Dih yd r o-5,7-d im e t h yl-1-n a p h t h yl)-1H -im id a -
zoliu m Ma lea te (5e). A solution of 10e (1.10 g, 2.3 mmol)
in 30 mL of TFA aqueous solution (60%) was stirred overnight.
The reaction was worked up in a manner similar to that
previously described for the synthesis of 5c. Removal of the
solvent gave 0.40 g (79%) of 5e as a free base, which was
converted to the maleate to afford the title compound as white
crystals: mp 149-150 °C; 1H NMR (300 MHz, CD3OD) δ 2.22
(s, 3H, CH3), 2.28 (s, 3H, CH3), 2.37-2.44 (m, 2H), 2.71-2.78
(m, 2H), 6.24 (s, 2H, HCdCH), 6.43 (t, J ) 4.81 Hz, 1H,
HCdC), 6.71 (s, 1H), 6.96 (s, 1H), 7.53 (d, J ) 1.35 Hz, 1H,
Im-H), 8.83 (d, J ) 1.35 Hz, 1H, Im-H); 13C NMR (300 MHz,
CD3OD) δ 19.62 (CH3), 21.11 (CH3), 23.91 (CH2), 24.12 (CH2),
170.71 (CdO); MS m/ e calcd for C15H16N2 (free base): 224,
found 224. Anal. (C19H20N2O4‚1/2H2O): C, H, N.
4-(5,7-Dim eth yl-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im i-
d a zoliu m Ma lea te (4e). A solution of 5e (free base, 0.25 g,
1.1 mmol) in absolute EtOH (10 mL) was shaken with 10%
palladium on charcoal (0.02 g) for 8 h under 40 psi of H2 on a
Parr hydrogenator. The solution was filtered through Celite
and the filtrate was evaporated to give 0.24 g (95%) of 4e as
a free base. The free base was converted to the maleate to
afford the title compound as white crystals: mp 138-139 °C;
1H NMR (300 MHz, CD3OD) δ 1.81-1.87 (m, 2H, CH2), 1.97-
2.00 (m, 1H), 2.06-2.11 (m, 1H), 2.17 (s, 3H, CH3), 2.21 (s,
3H, CH3), 2.65-2.70 (m, 2H, Ar-CH2), 4.30 (t, J ) 6.02 Hz,
1H, CH), 6.24 (s, 2H, HCdCH), 6.60 (s, 1H), 6.89 (s, 1H), 7.03-
7.04 (m, 1H), 8.73 (d, J ) 1.36 Hz, 1H, Im-H); 13C NMR (300
MHz, CD3OD) δ 19.62 (CH3), 20.91 (CH3), 21.42, 27.09, 30.87,
37.44, 170.78 (CdO); IR (KBr) 1570, 1516, 1481 cm-1; MS
m/ e calcd for C15H18N2 (free base): 226, found 226. Anal.
(C19H22N2O4): C, H, N.
4-(5-Meth yl-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im id a -
zoliu m Ma lea te (4c). To a solution of 5c (free base, 0.24 g,
1.1 mmol) in absolute EtOH (10 mL) was added 10% Pd/C (0.02
g). The mixture was subjected to 40 psi of H2 for 5 h. The
mixture was filtered through Celite, and the solvent was
evaporated to give 0.23 g (98%) of 5c as a free base. The free
base was converted immediately to the maleate to afford the
1
title compound as white crystals: mp 144-145 °C; H NMR
(300 MHz, CD3OD) δ 1.84-1.90 (m, 2H, CH2), 2.00-2.03 (m,
1H), 2.09-2.14 (m, 1H), 2.25 (s, 3H, CH3), 2.70-2.76 (m, 2H,
Ar-CH2), 4.35 (t, J ) 6.08 Hz, 1H, CH), 6.24 (s, 2H, HCdCH),
6.78 (d, J ) 7.20 Hz, 1H), 6.98-7.07 (m, 3H), 8.75 (d, J ) 1.42
Hz, 1H, Im-H); 13C NMR (300 MHz, CD3OD) δ 19.70 (CH3),
21.38, 27.41, 30.78, 37.48, 170.77 (CdO); IR (KBr) 1571, 1507,
1458 cm-1; MS m/ e calcd for C14H16N2 (free base): 212, found
212. Anal. (C18H20N2O4): C, H, N.
4-[1-(5,7-Dim eth yl-1-h yd r oxy-1,2,3,4-tetr a h yd r on a p h -
th yl)]-N-(tr ip h en ylm eth yl)im id a zole (10e). A 3.0 M solu-
tion of EtMgBr (1.4 mL, 4.2 mmol) in Et2O was added to a
0.25 M solution of 4-iodo-N-(triphenylmethyl)imidazole (1.69
g, 3.9 mmol) in dry CH2Cl2 at ambient temperature. After 1
h, a solution of 5,7-dimethyl-1-tetralone (9e, 0.45 g, 2.6 mmol)
in 2 mL of dry CH2Cl2 was added, and stirring was continued
overnight. The reaction was worked up in a manner similar
to that previously described for the synthesis of 9c. The crude
product was recrystallized from CH2Cl2/hexane to provide 1.17
g (94%) of the title compound as a white solid: mp 140-141
°C; 1H NMR (300 MHz, CDCl3) δ 1.74-1.78 (m, 1H), 1.99-
2.10 (m, 2H, CH2), 2.15 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.26-
2.32 (m, 1H), 2.56-2.66 (m, 2H, CH2), 3.20 (bs, 1H, OH), 6.44
(d, J ) 1.45 Hz, 1H, Im-H), 6.83 (s, 1H), 6.96 (s, 1H), 7.10-
5-(Ben zyloxy)-1-tetr a lon e (9d ). A mixture of 70 mL of
CHCl3/MeOH (2:1) and anhydrous K2CO3 (3.01 g, 21.8 mmol)
was heated to reflux for 15 min under argon. Benzyl bromide
(0.65 mL, 5.5 mmol) and a solution of 5-hydroxy-1-tetralone
(0.81 g, 5 mmol) in 20 mL of CHCl3/MeOH (2:1) were added,
and the mixture was heated at reflux for an additional 3 h.
After filtration, the filtrate was evaporated, and the residue
was dissolved in CHCl3, washed with HCl (1 N), dried, and
concentrated. Flash chromatography of the crude product,
eluting with EtOAc/hexane (1:6), gave 1.12 g (89%) of 9d as
white crystals: mp 50-51.5 °C; 1H NMR (300 MHz, CDCl3) δ
2.08-2.16 (m, 2H, CH2), 2.62-2.66 (m, 2H, COCH2), 2.97 (t,
J ) 6.14 Hz, 2H, ArCH2), 5.11 (s, 2H, OCH2), 7.08 (dd, J )
1.11, 8.09 Hz, 1H, o-(OBn)), 7.23-7.28 (m, 1H, m-(OBn)), 7.32-
7.46 (m, 5H), 7.68 (dd, J ) 1.04, 7.88 Hz, 1H, p-(OBn)); IR

3022 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Zhang et al.
(KBr) 1684 cm-1; MS m/ e calcd for C17H16O2: 252, found 252.
Anal. (C17H16O2): C, H.
25 mL of TFA aqueous solution (60%) was stirred overnight.
The reaction was worked up in a manner similar to that
previously described for the synthesis of 5c. Removal of the
solvent gave 0.51 g (90%) of 4-(3,4-dihydro-5-methoxy-1-
naphthyl)-1H-imidazole (5b) as white crystals: 1H NMR (300
MHz, CD3OD) δ 2.26-2.33 (m, 2H, CH2), 2.77 (t, J ) 7.75 Hz,
2H, ArCH2), 3.83 (s, 3H, OCH3), 6.28 (t, J ) 4.72 Hz, 1H,
HCdC), 6.86 (d, J ) 7.95 Hz, 2H), 7.01 (s, 1H, Im-H), 7.10 (t,
J ) 7.92 Hz, 1H), 7.66 (s, 1H, Im-H). The product was used
in the following step without further characterization.
4-[1-[5-(Ben zyloxy)-1-h yd r oxy-1,2,3,4-tetr a h yd r on a p h -
th yl]-N-(tr ip h en ylm eth yl)im id a zole (10d ). A 3.0 M solu-
tion of EtMgBr (2 mL, 6 mmol) in Et2O was added to a 0.25 M
solution of 4-iodo-N-(triphenylmethyl)imidazole (2.40 g, 5.5
mmol) in dry CH2Cl2 at ambient temperature. After 1 h, a
solution of 5-(benzyloxy)-1-tetralone (9d , 0.89 g, 3.5 mmol) in
2 mL of dry CH2Cl2 was added, and stirring was continued
overnight. The reaction was worked up in a manner similar
to that previously described for the synthesis of 9c. The crude
product was recrystallized from CH2Cl2/hexane to provide 1.66
g (84%) of the title compound as a white solid: mp 147-148
°C dec; 1H NMR (300 MHz, CDCl3) δ 1.70-1.75 (m, 1H), 1.95-
2.00 (m, 1H), 2.05-2.13 (m, 1H), 2.29-2.37 (m, 1H), 2.66-
2.74 (m, 1H), 2.81-2.91 (m, 1H), 3.22 (bs, 1H, OH), 5.03 (s,
2H, OCH2), 6.45 (d, J ) 1.45 Hz, 1H, Im-H), 6.74 (dd, J )
2.04, 1.07 Hz, 1H), 6.96-6.99 (m, 1H), 7.05-7.14 (m, 6H),
7.29-7.34 (m, 10H), 7.37-7.44 (m, 5H); IR (KBr) 3233, 1493,
1473, 1450 cm-1; MS m/ e: 243(Tr+). Anal. (C39H34N2O2‚1/
2H2O): C, H, N.
4-[3,4-Dih yd r o-5-(b en zyloxy)-1-n a p h t h yl]-1H -im id a -
zoliu m Ma lea te (5d ). A solution of 10d (1.0 g, 1.8 mmol) in
20 mL of TFA aqueous solution (60%) was stirred overnight.
The reaction was worked up in a manner similar to that
previously described for the synthesis of 5c. Removal of the
solvent gave 0.50 g (92%) of 5d as a free base, which was
converted to the maleate to afford the title compound as white
crystals: mp 168-169 °C; 1H NMR (300 MHz, CD3OD) δ 2.39-
2.42 (m, 2H, CH2), 2.89 (t, J ) 7.84 Hz, 2H, Ar-CH2), 5.14 (s,
2H, OCH2), 6.25 (s, 2H, HCdCH), 6.47 (t, J ) 4.77 Hz, 1H,
HCdC), 6.70 (d, J ) 7.20 Hz, 1H), 7.03 (d, J ) 7.51 Hz, 1H),
7.15 (t, J ) 7.77 Hz, 1H), 7.30-7.40 (m, 3H), 7.43-7.46 (m,
2H), 7.53 (d, J ) 1.35 Hz, 1H, Im-H), 8.81 (d, J ) 1.36 Hz,
1H, Im-H); 13C NMR (300 MHz, CD3OD) δ 20.54 (CH2), 23.72
(CH2), 71.46 (OCH2), 170.69 (CdO); IR (KBr) 1569, 1508, 1467
cm-1; MS m/ e calcd for C20H18N2O (free base): 302, found 302.
Anal. (C24H22N2O5): C, H, N.
A solution of 5b (free base, 0.51 g, 2.3 mmol) in absolute
EtOH (10 mL) was shaken with 10% palladium on charcoal
(0.05 g) for 12 h under 30 psi of H2 on a Parr hydrogenator.
The solution was filtered through Celite, and the filtrate
was evaporated to give 0.51 g (99%) of 4b as a free base. The
free base was converted to the maleate to afford the title
1
compound as white crystals: mp 149-150 °C; H NMR (300
MHz, CD3OD) δ 1.78-1.84 (m, 2H, CH2), 1.97-2.01 (m, 1H),
2.07-2.14 (m, 1H), 2.72 (t, J ) 6.54 Hz, 2H, ArCH2), 3.82 (s,
3H, OCH3), 4.33 (t, J ) 6.21 Hz, 1H, CH), 6.24 (s, 2H,
HCdCH), 6.53 (d, J ) 7.78 Hz, 1H), 6.81 (d, J ) 8.10 Hz, 1H),
7.07-7.12 (m, 2H), 8.73 (d, J ) 1.39 Hz, 1H, Im-H); 13C NMR
(300 MHz, CD3OD) δ 20.94, 23.87, 30.85, 37.13, 55.83 (OCH3),
170.77 (CdO); MS m/ e calcd for C14H16N2O (free base): 228,
found 228. Anal. (C18H20N2O5): C, H, N.
4-[1-(1-Hyd r oxy-6-m eth oxy-1,2,3,4-tetr a h yd r on a p h th -
yl)]-N-(tr ip h en ylm eth yl)im id a zole (10f). A 3.0 M solution
of EtMgBr (1.6 mL, 4.8 mmol) in Et2O was added to a 0.25 M
solution of 4-iodo-N-(triphenylmethyl)imidazole (2.1 g, 4.8
mmol) in dry CH2Cl2 at ambient temperature. After 1 h, a
solution of 6-methoxy-1-tetralone (9f, 0.56 g, 3.2 mmol) in 2
mL of dry CH2Cl2 was added, and stirring was continued
overnight. The reaction was worked up in a manner similar
to that previously described for the synthesis of 9c. The crude
product was recrystallized from CH2Cl2/hexane to provide 1.29
g (84%) of the title compound as a white solid: mp 93-95 °C;
1H NMR (300 MHz, CDCl3) δ 1.62-1.73 (m, 1H), 1.91-2.03
(m, 1H), 2.04-2.15 (m, 1H), 2.26-2.38 (m, 1H), 2.77-2.79 (m,
2H, Ar CH2), 3.16 (bs, 1H, OH), 3.75 (s, 3H, OCH3), 6.46 (d, J
) 1.44 Hz, 1H, Im-H), 6.56 (d, J ) 2.63 Hz, 1H, o-(OCH3)),
6.65 (dd, J ) 2.70, 8.65 Hz, 1H, o-(OCH3)), 7.10-7.15 (m, 6H,
Tr-H), 7.21 (d, J ) 8.65 Hz, 1H, m-(OCH3)), 7.29-7.34 (m, 9H,
Tr-H), 7.37 (d, J ) 1.43 Hz, 1H, Im-H); IR (KBr) 3214, 1500,
1445 cm-1; MS m/ e calcd for C33H30N2O2: 487, found 487.
Anal. (C33H30N2O2‚1/4H2O‚1/2CH2Cl2): C, H, N.
4-(5-Hyd r oxy-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im id a -
zoliu m Ma lea te (4d ). A solution of 5d (free base, 0.40 g, 1.3
mmol) in absolute EtOH (10 mL) was shaken with 10%
palladium on charcoal (0.02 g) for 32 h under 40 psi of H2 on
a Parr hydrogenator. The solution was filtered through Celite,
and the filtrate was evaporated to give 0.20 g (71%) of the free
base, which was converted to the maleate to afford the title
1
compound as white crystals: mp 138-140 °C; H NMR (300
4-(6-Me t h o x y -3,4-d ih y d r o -1-n a p h t h y l)-1H -im id a -
zoliu m Ma lea te (5f). A solution of 10f (1.15 g, 2.4 mmol) in
20 mL of TFA aqueous solution (60%) was stirred overnight.
The reaction was worked up in a manner similar to that
previously described for the synthesis of 5c. Removal of the
solvent gave 0.33 g (61%) of 5f (free base). The free base was
converted to the maleate to afford the title compound as white
crystals: mp 152-153 °C; 1H NMR (300 MHz, CD3OD) δ 2.40-
2.42 (m, 2H, CH2), 2.82 (t, J ) 7.67 Hz, 2H, CH2), 3.79 (s, 3H,
OCH3), 6.25 (s, 2H, HCdCH), 6.31 (t, J ) 4.80 Hz, 1H, HCdC),
6.74- 6.77 (m, 1H), 6.83 (d, J ) 2.59 Hz, 1H), 7.02 (d, J )
8.50 Hz, 1H), 7.52 (d, J ) 1.34 Hz, 1H), 8.78 (d, J ) 1.36 Hz,
1H); 13C NMR (300 MHz, CD3OD) δ 26.66 (CH2), 31.43 (CH2),
MHz, CD3OD) δ 1.76-1.86 (m, 2H, CH2), 1.91-2.04 (m, 1H),
2.05-2.17 (m, 1H), 2.73 (t, J ) 6.55 Hz, 2H, Ar-CH2), 4.31 (t,
J ) 13.12 Hz, 1H, CH), 6.25 (s, 2H, HCdCH), 6.41 (d, J )
7.71 Hz, 1H), 6.66 (d, J ) 7.87 Hz, 1H), 6.93 (t, J ) 7.88 Hz,
1H), 7.09 (d, J ) 0.68 Hz, 1H, Im-H), 8.75 (d, J ) 1.33 Hz,
1H, Im-H); 13C NMR (300 MHz, CD3OD) δ 21.11, 23.95, 31.03,
37.16, 170.72 (CdO); MS m/ e calcd for C13H14N2O (free base):
214, found 214; Anal. (C17H18N2O5‚1/4H2O): C, H, N.
4-[1-(1-Hyd r oxy-5-m eth oxy-1,2,3,4-tetr a h yd r on a p h th -
yl)]-N-(tr ip h en ylm eth yl)im id a zole (10b). A 3.0 M solution
of EtMgBr (1.6 mL, 4.8 mmol) in Et2O was added to a 0.25 M
solution of 4-iodo-N-(triphenylmethyl)imidazole (2.1 g, 4.8
mmol) in dry CH2Cl2 at ambient temperature. After 1 h, a
solution of 5-methoxy-1-tetralone (9b, 0.56 g, 3.2 mmol) in 2
mL of dry CH2Cl2 was added, and stirring was continued
overnight. The reaction was worked up in a manner similar
to that previously described for the synthesis of 9c. The crude
product was recrystallized from CH2Cl2/hexane to provide 1.33
g (91%) of the title compound as a white solid: mp 130-132
°C; 1H NMR (300 MHz, CDCl3) δ 1.70-1.77 (m, 1H), 1.93-
1.98 (m, 1H), 2.03-2.11 (m, 1H), 2.29-2.35 (m, 1H), 2.54-
2.64 (m, 1H), 2.71-2.79 (m, 1H), 3.24 (bs, 1H, OH), 3.78 (s,
OCH3), 6.44 (d, J ) 1.48 Hz, 1H, Im-H), 6.67 (dd, J ) 8.03,
1.03 Hz, 1H, o-(OCH3)), 6.95 (dd, J ) 7.92, 1.04 Hz, 1H,
p-(OCH3)), 7.06 (d, J ) 7.98 Hz, 1H, m-(OCH3)), 7.09-7.13 (m,
6H, Tr-H), 7.28-7.33 (m, 9H, Tr-H), 7.37 (d, J ) 1.46 Hz, 1H,
Im-H). The product was used in the synthesis of 4b without
further characterization.
58.21 (OCH3), 170.75 (CdO); IR (KBr) 1566, 1508, 1459 cm-1
;
MS m/ e calcd for C14H14N2O (free base): 226, found 226. Anal.
(C18H18N2O5): C, H, N.
4-(6-Meth oxy-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im id a -
zoliu m Ma lea te (4f). A solution of 5f (free base, 0.24 g, 1.1
mmol) in absolute EtOH (10 mL) was shaken with 10%
palladium on charcoal (0.02 g) for 12 h under 30 psi of H2 on
a Parr hydrogenator. The solution was filtered through Celite,
and the filtrate was evaporated to give 0.23 g (96%) of 4f as a
free base. The free base was converted to the maleate to afford
the title compound as white crystals: mp 138-139 °C; 1H NMR
(300 MHz, CD3OD) δ 1.78-1.84 (m, 2H, CH2), 1.96-2.00 (m,
1H), 2.11-2.15 (m, 1H), 2.81-2.88 (m, 2H, CH2), 3.75 (s, 3H,
OCH3), 4.28 (t, J ) 6.33 Hz, 1H, CH), 6.24 (s, 2H, HCdCH),
6.68-6.71 (m, 2H), 6.84 (d, J ) 8.25 Hz, 1H), 7.07 (dd, J )
1.35, 0.63 Hz, 1H), 8.75 (d, J ) 1.42 Hz, 1H); 13C NMR (300
MHz, CD3OD) δ 21.60, 30.45, 31.58, 36.42, 55.61 (OCH3),
4-(5-Meth oxy-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im id a -
zoliu m Ma lea te (4b). A solution of 10b (1.2 g, 2.5 mmol) in

Medetomidine Analogs as R2-Adrenergic Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3023
170.78 (CdO); MS m/ e calcd for C14H16N2O (free base): 228,
found 228. Anal. (C18H18N2O5): C, H, N.
61.44 (OCH2), 168.99 (CdO); IR (neat) 1734 cm-1; MS m/ e
calcd for C15H20O4: 264, found 264. Anal. (C15H20O4): C, H.
3-(2-Meth ylp h en yl)p r op ion ic Acid (12). To a potassium
hydroxide aqueous solution (18 M, 10 mL) was added diethyl
(2-methylbenzyl)malonate (11, 7.0 g, 26.5 mmol). The solution
was heated to reflux for 1.5 h and then diluted with 20 mL of
water and evaporated to remove the ethanol formed in the
hydrolysis. To the cold solution was added slowly a H2SO4
aqueous solution (7.0 M, 35 mL), and the mixture was heated
to reflux for 5 h. After cooling, the aqueous solution was
extracted with Et2O (3 × 100 mL). The combined organics
were washed with water, dried over Na2SO4, and concentrated.
The crude product was a mixture of diacid and monoacid,
which was placed in a flask and heated to 160 °C under argon.
Evolution of CO2 was observed at 140 °C and became vigorous
as the material melted. The reaction was maintained at 160
°C for 30 min and cooled to room temperature with stirring to
yield a light-yellow solid, which was then crystallized in Et2O/
hexane to give 3.55 g (82%) of the product as white needles:
mp 99-100 °C (lit.23 102-104 °C); 1H NMR (300 MHz, CDCl3)
δ 2.33 (s, 3H, CH3), 2.62-2.68 (m, 2H, CH2), 2.93-2.99 (m,
2H, CH2), 7.15 (s, 4H, Ar-H); IR (KBr) 1700 cm-1; MS m/ e
calcd for C10H12O2: 164, found 164. Anal. (C10H12O2): C, H.
4-Meth yl-1-in d a n on e (13). A solution of 3-(2-methylphen-
yl)propionic acid (12, 0.84, 5.1 mmol) in 10 mL of SOCl2 was
heated at reflux for 1 h. Excess SOCl2 was evaporated under
the reduced pressure to give 3-(2-methylphenyl)propionic acid
chloride as a light brown oil: 1H NMR (300 MHz, CDCl3) δ
2.32 (d, J ) 2.18 Hz, 3H, CH3), 2.99-3.04 (m, 2H, CH2), 3.14-
3.19 (m, 2H, CH2), 7.13-7.17 (m, Ar-H). This product was
dissolved in 65 mL of dry CH2Cl2 and used immediately in
the following step.
Titanium tetrachloride (1.2 mL, 11 mmol) was added
dropwise to the above solution at -30 °C under argon. The
mixture was stirred at -30 °C for an additional 30 min and
then was warmed to room temperature. Stirring was contin-
ued for 2 days. The resulting brown mixture was carefully
poured into 150 mL of crushed ice and stirred until the dark
color disappeared. The layers were separated, and the aque-
ous portion was extracted with CH2Cl2 (3 × 100 mL). The
combined organics were washed successively with H2O, HCl
solution (10%), H2O, saturated aqueous NaHCO3 solution, and
brine. After drying over Na2SO4, the solution was concen-
trated under the reduced pressure to give 0.63 g (86%) of 13
as a white solid: mp 93-94 °C; 1H NMR (300 MHz, CDCl3) δ
2.37 (s, 3H, CH3), 2.69-2.73 (m, 2H, CH2), 3.03 (t, J ) 5.46
Hz, 2H, CH2), 7.30 (t, J ) 7.50 Hz, 1H, m-(CH3)), 7.41 (d, J )
7.20 Hz, 1H, o-(CH3)), 7.61 (d, J ) 7.57 Hz, 1H, p-(CH3)); IR
(KBr) 1702 cm-1; MS m/ e calcd for C10H10O: 146, found 146.
This compound was used in the synthesis of 14 without further
characterization.
4-[1-(1-Hyd r oxy-7-m eth oxy-1,2,3,4-tetr a h yd r on a p h th -
yl)]-N-(tr ip h en ylm eth yl)im id a zole (10g). A solution of
4-iodo-N-(triphenylmethyl)imidazole (2.3 g, 5.3 mmol) in dry
CH2Cl2 at ambient temperature. After 1 h, a solution of
7-methoxy-1-tetralone (9g, 0.61 g, 3.5 mmol) in 2 mL of dry
CH2Cl2 was added, and stirring was continued overnight. The
reaction was worked up in a manner similar to that previously
described for the synthesis of 9c. The crude product was
recrystallized from CH2Cl2/hexane to provide 1.35 g (80%) of
the title compound as a white solid: mp 180-181 °C; 1H NMR
(300 MHz, CDCl3) δ 1.66-1.76 (m, 1H), 1.87-2.03 (m, 1H),
2.05-2.16 (m, 1H), 2.27-2.40 (m, 1H), 2.62-2.84 (m, 2H,
CH2), 3.24 (bs, 1H, OH), 3.67 (s, 3H, OCH3), 6.42 (d, J ) 1.48
Hz, 1H, Im-H), 6.70 (dd, J ) 2.78, 8.40 Hz, 1H, o-(OCH3)),
6.86 (d, J ) 2.75 Hz, 1H, o-(OCH3)), 6.95 (d, J ) 8.45 Hz,
1H, m-(OCH3)), 7.10-7.14 (m, 6H, Tr-H), 7.29-7.33 (m, 9H,
Tr-H), 7.40 (d, J ) 1.47 Hz, 1H, Im-H); IR (KBr) 3197, 1500,
1445 cm-1; MS m/ e calcd for C33H30N2O2: 487, found 487.
Anal. (C33H30N2O2‚1/2H2O): C, H, N.
4-(3,4-D ih y d r o -7-m e t h o x y -1-n a p h t h y l)-1H -im id a -
zoliu m Ma lea te (5g). A solution of 10g (0.5 g, 2.1 mmol) in
10 mL of TFA aqueous solution (60%) was stirred overnight.
The reaction was worked up in a manner similar to that
previously described for the synthesis of 5c. Removal of the
solvent gave 0.17 g (74%) of 5g (free base). The free base was
converted to the maleate to afford the title compound as white
crystals: mp 154-155 °C; 1H NMR (300 MHz, CD3OD) δ 2.43-
2.46 (m, 2H, CH2), 2.80 (t, J ) 7.64 Hz, 2H, Ar-CH2), 3.75 (s,
3H, OCH3), 6.27 (s, 2H, HCdCH), 6.51 (t, J ) 4.80 Hz, 1H,
HCdC), 6.65 (d, J ) 2.56 Hz, 1H, o-(OCH3)), 6.83 (dd, J )
8.25, 2.59 Hz, 1H, o-(OCH3)), 7.19 (d, J ) 8.24 Hz, 1H,
m-(OCH3)), 7.59 (d, J ) 1.27 Hz, 1H, Im-H), 8.85 (d, J )
1.31 Hz, 1H, Im-H); 13C NMR (300 MHz, CD3OD) δ 24.63
(CH2), 27.52 (CH2), 55.76 (OCH3), 170.68 (CdO); MS m/ e
calcd for C14H16N2O (free base, MH+): 227, found 227. Anal.
(C18H18N2O5): C, H, N.
4-(7-Meth oxy-1,2,3,4-tetr a h yd r o-1-n a p h th yl)-1H-im id a -
zoliu m Ma lea te (4g). A solution of 5g (free base, 0.25 g, 1.1
mmol) in absolute EtOH (10 mL) was shaken with 10%
palladium on charcoal (0.02 g) for 5 h under 30 psi of H2 on a
Parr hydrogenator. The solution was filtered through Celite,
and the filtrate was evaporated to give 0.25 g (99%) of the
product (free base). The free base was converted to the
maleate to afford the title compound as white crystals: mp
121-122 °C; 1H NMR (300 MHz, CD3OD) δ 1.80-1.83 (m, 2H,
CH2), 1.96-2.00 (m, 1H), 2.12-2.16 (m, 1H), 2.77-2.83 (m,
2H, Ar-CH2), 3.67 (s, 3H, OCH3), 4.33 (t, J ) 6.27 Hz, 1H, CH),
6.24 (s, 2H, HCdCH), 6.46 (d, J ) 2.56 Hz, 1H), 6.78 (dd, J )
8.45, 2.65 Hz, 1H), 7.07-7.11 (m, 2H), 8.75 (d, J ) 1.35 Hz,
1H, Im-H); 13C NMR (300 MHz, CD3OD) δ 21.85, 29.30, 31.38,
4-[1-(1-Hyd r oxy-4-m eth ylin d a n yl)]-N-(tr ip h en ylm eth -
yl)im id a zole (14). A 3.0 M solution of EtMgBr (2.7 mL, 8.1
mmol) in Et2O was added to a 0.25 M solution of 4-iodo-N-
(triphenylmethyl)imidazole (3.48 g, 8.0 mmol) in dry CH2Cl2
at ambient temperature. After 1 h, a solution of 4-methyl-1-
indanone (13, 0.60 g, 4.1 mmol) in 2 mL of dry CH2Cl2 was
added, and stirring was continued overnight. The reaction
37.32, 55.64 (OCH3), 170.77 (CdO); IR (KBr) 1565, 1494 cm-1
;
MS m/ e calcd for C14H16N2O (free base): 228, found 228. Anal.
(C18H20N2O5): C, H, N.
Dieth yl (2-Meth ylben zyl)m a lon a te (11). A concentrated
sodium ethoxide solution (21% in EtOH, 51 mmol) was diluted
with 14 mL of absolute EtOH under argon. Freshly distilled
diethyl malonate (7.8 mL, 51 mmol) was added dropwise at
70 °C to the above solution. After 10 min, 2-methylben-
zyl chloride (6.6 mL, 51 mmol) was added while refluxing over
a period of 15 min. The reaction mixture was stirred at
refluxing condition for another 2 h and quenched with water
at room temperature. The mixture was neutralized with
aqueous HCl (6 N) and concentrated to remove EtOH. The
residue was partitioned between 50 mL of H2O and 100 mL of
Et2O. The water layer was extracted with Et2O (3 × 50 mL),
and the combined organics were washed with brine, dried over
Na2SO4, and concentrated. The crude product was distilled
to yield 7.49 g (57%) of the product as a colorless oil: bp 155-
was worked up in
a manner similar to that previously
described for the synthesis of 9c. The crude product was
recrystallized from CH2Cl2/hexane to provide 1.15 g (61%) of
the title compound as a white solid: mp 126-128 °C; 1H NMR
(300 MHz, CDCl3) δ 2.26 (s, 3H, CH3), 2.42-2.49 (m, 1H),
2.59-2.69 (m, 1H), 2.83-2.84 (m, 1H), 3.02-3.10 (m, 1H), 6.69
(d, J ) 1.41 Hz, 1H, Im-H), 7.02-7.08 (m, 3H), 7.11-7.14 (m,
6H), 7.30-7.34 (m, 9H), 7.40 (d, J ) 1.38 Hz, 1H, Im-H); IR
(KBr) 3282, 1494, 1444 cm-1; MS m/ e: 438 (M - H2O). Anal.
(C32H28N2O‚1/4H2O): C, H, N.
4-[1-(4-Meth ylin d a n yl)]-1H-im id a zoliu m Ma lea te (6).
To a mixture of Me3SiCl (1.68 mL, 13.2 mmol), NaI (2.0 g 13.2
mmol), and dry CH3CN (0.5 mL, 13.2 mmol) was added a
1
160 °C at 3 mmHg; H NMR (300 MHz, CDCl3) δ 1.20 (t, J )
Cl2 (5 mL). The
solution of 14 (1.0 g, 2.2 mmol) in dry CH2
7.14 Hz, 6H, 2CH3), 2.34 (s, 3H, Ar-CH3), 3.22 (d, J ) 7.79
Hz, 2H, Ar-CH2), 3.64 (t, J ) 7.82 Hz, 1H, CH), 4.11-4.19 (m,
4H, 2OCH2), 7.08-7.14 (m, 4H, Ar-H); 13C NMR (300 MHz,
CDCl3) δ 13.97 (CH3), 19.29 (CH3), 31.89 (CH2), 52.26 (CH),
mixture was stirred for 24 h at room temperature. Dilution
with H2O, extraction with CH2Cl2, and subsequent flash
chromatography, eluting with CH2Cl2/CH3OH (20:1), gave 0.33
g (76%) of 6 (free base) as a white solid. The free base was

3024 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Zhang et al.
(4) Miller, D. D.; Zhang, X.; Matsumoto, K.; Hsu, F.-L. Synthesis of
Naphthalene Analogs of Medetomidine as R2-Adrenergic Agonist.
Proceeding of the 1992 U.S. Army Chemical Research, Develop-
ment and Engineering Center Scientific Conference on Chemical
Defense Research; U.S. Army Chemical and Biological Defense
Agency: Aberdeen Proving Grounds, MD, 1992; pp 467-472.
(5) Unpublished data.
(6) Hibert, M. F.; Trumpp-Kallmeyer, S.; Bruinvels, A.; Hoflack, J .
Three-dimensional Models of Neurotransmitter G-binding Protein-
Coupled Receptors. Mol. Pharmacol. 1991, 40, 8-15.
(7) Trumpp-Kallmeyer, S.; Hoflack, J .; Bruinvels, A.; Hibert, M. F.
Modeling of G-Protein-Coupled Receptors: Application to Dop-
amine, Adrenaline, Serotonine, Acetylcholine, and Mammalian
Opsin Receptors. J . Med. Chem. 1992, 35, 3448-3462.
(8) Turner, R. M.; Lindell, S. D. A Facile Route to Imidazol-4-yl
Anions and Their Reaction with Carbonyl Compounds. J . Org.
Chem. 1991, 56, 5739-5740.
(9) Sakai, T.; Miyata, K.; Utaka, M.; Takeda, A. Me3SiCl-NaI-
CH3CN as an Efficient and Practical Reducing Agent for
Benzylic Alcohols. Tetrahedron Lett. 1987, 28, 3817-3818.
(10) Dohlman, H. G.; Caron, M. G.; Lefkowitz, R. J . A Family of
Receptors Coupled to Guanine Nucleotide Regulatory Proteins.
Biochemistry 1987, 26, 2657-2664.
(11) Henderson, R.; Baldwin, J .; Ceska, T. H.; Zemlin, F.; Beckmann,
E.; Downing, K. Model for the Structure of Bacteriorhodopsin
Based on High Resolution Electron Cryomicroscopy. J . Mol. Biol.
1990, 213, 899-929.
(12) Wang, C. D.; Buck, M. A.; Fraser, C. M. Site-Directed Mutagen-
esis of R2A-Adrenergic Receptors: Identification of Amino Acids
Involved in Ligand Binding and Receptor Activation by Agonists.
Mol. Pharmacol. 1991, 40, 168-179.
(13) Li, Y. O.; Bergsma, D. J .; Ganguly, S.; Swift, A. M.; Ruffolo, R.
R., J r.; Hieble, J . P. Effect of Point Mutation in Transmembrane
Helices II and II on the Stereoselective Interaction of Catechola-
mines with the R2A-Adrenoceptor, Proceedings of the XII Inter-
national Congress of Pharmacology, Montreal, Canada, J uly 24-
29, 1994.
(14) Ruffolo, R. R., J r.; Waddell, J . E. Stereochemical Requirements
of R2-Adrenergic Receptors for R-Methyl Substituted Pheneth-
ylamines. Life Sci. 1982, 31, 2999-3007.
(15) Graham, R. M.; Neubig, R.; Lynch, K. R. R2-Adrenoceptors Take
Center Stage at Nashville Meeting. Trends Pharmacol. Sci.
1996, 17, 90-94.
converted to the maleate and the salt was recrystallized in
1
CH3OH/Et2O: mp 127-129 °C; H NMR (300 MHz, CD3OD)
δ 2.10-2.18 (m, 1H), 2.29 (s, 3H, CH3), 2.60-2.65 (m,
1H), 2.91-2.96 (m, 1H), 3.00-3.05 (m, 1H), 4.58 (t, J
)
8.12 Hz, 1H, CH), 6.24 (s, 2H, HCdCH), 6.88 (d, J ) 6.98
Hz, 1H), 7.04-7.12 (m, 2H), 7.27 (d, J ) 1.29 Hz, 1H, Im-H),
8.77 (d, J ) 1.35 Hz, 1H, Im-H); 13C NMR (300 MHz, CD3OD)
δ 19.07 (CH3), 30.81, 34.16, 42.78, 170.77 (CdO); MS m/ e
calcd for C13H14N2 (free base, MH+): 199, found 199. Anal.
(C17H18N2O4‚1/4H2O): C, H, N.
Ra d ioliga n d Bin d in g Stu d ies. All of the newly synthetic
imidazoles were determined on R1- and R2-adrenoceptor sys-
tems using membrane fractions of rat brain, as described
previously.3
Recep tor Mod elin g. The receptor model was constructed
using SYBYL 5.5 (TRIPOS associates Inc.). The coordinates
for bacteriorhodopsin were obtained from Brookhaven Protein
Data Bank. The amino acid sequence for the human R2-
adrenoceptor was obtained from Hibert et al.6 The receptor
model of the human R2-adrenoceptor was constructed in a
similar way according to a strategy previously described by
Hibert et al.6 In short, the model was based on a presumed
similarity in three-dimensional structure between bacterio-
rhodopsin and the GPC receptors. R-Helices were constructed
from the primary structure of the human R2-adrenoceptor with
φ and ψ values of -59° and -44°, and the proline kinks were
fixed. Each helices were energy minimized using Kollmann
all-atom force field in SYBYL. Fitting of the backbone of these
helices onto the backbone of bacteriorhodopsin in such a way
that the conserved residues were oriented toward the inside
of the receptor, as were the charged amino acids. The loop
regions of the receptor were not included in the modeling.
Finally, the resulting bundle of the receptor was energy
minimized by Kollmann all-atom force field for 2000 steps
using conjugate gradient minimizer. A cutoff of 8 Å was used.
Bin d in g Site Mod elin g. The conformational analysis of
R-MeNE and the medetomidine-like analogs have been de-
scribed previously.3 The low-energy conformation of R-MeNE
was docked into the receptor model manually. The potential
interactions of R-MeNE with R2-adrenoceptor derived by site-
directed mutagenesis was considered during the docking
procedure. The complex of receptor-ligand was optimized by
Tripos force field. The low-energy conformations of (S)-
medetomidine and its analogs were aligned with the one of
R-MeNE by fitting the aromatic ring and the nitrogen atom
and then used in the docking.
(16) Mizobe, T.; Maze, M.; Lam, V.; Suryanayana, S.; Kobilka, B. K.
Arrangement of Transmembrane Domains in Adrenergic Recep-
tors. J . Biol. Chem. 1996, 271, 2387-2389.
(17) Woodward, R.; Coley, C.; Daniell, S.; Naylor, L. H.; Strange, P.
G. Investigation of the Role of Conserved Serine Residues in the
Long Form of the Rat D2 Dopamine Receptor Using Site-directed
Mutagenesis. J . Neurochem. 1996, 66, 394-402.
(18) Strange, P. G. The Energetics of Ligand Binding at Catechol-
amine Receptors. Trends Pharmacol. Sci. 1996, 17, 238-
241.
(19) Strader, C. D.; Candelore, M. R.; Hill, W. S.; Sigal, I. S.; Dixon,
R. A. Identification of Two Serine Residues Involved in Agonist
Activation of the Beta-adrenergic Receptor. J . Biol. Chem. 1989,
264, 13572-8.
(20) Morin, F. G.; Horton, W. J .; Grant, D. M.; Dalling, D. K.;
Pugmire, R. J . Carbon-13 Magnetic Resonance of Hydroaromat-
ics. 2. Conformation of Tetralin and Tetrahydroanthracene and
Their Methyl Derivatives. J . Am. Chem. Soc. 1983, 105, 3992-
3998.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 29358-12) and the U.S. Army
Chemical Research, Development and Engineering Cen-
ter, Aberdeen Proving Ground, for support of this
research project.
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