Synthesis and dopaminergic properties of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine, a potent and selective dopamine D4 receptor ligand

Article abstract of DOI:10.1016/S0960-894X(00)00633-8

The synthesis of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine 1, a potent and selective D4 dopaminergic ligand, was performed. The 3-(3,4-dimethylphenyl)-1-propylpiperidine with the R configuration showed an affinity for the D4 receptors 6-fold higher than the corresponding enantiomer with the S configuration. Furthermore, the (R)-1 enantiomer proved to be highly selective for D4 receptors with respect to D2-D3 receptors, with a K_i ratio higher than 25,000, while the (S)-1 enantiomer was about 100-fold less selective than the (R)-1 one.

Full text of DOI:10.1016/S0960-894X(00)00633-8

Bioorganic & Medicinal Chemistry Letters 11 (2001) 223±226
Synthesis and Dopaminergic Properties of the Two Enantiomers of
3-(3,4-Dimethylphenyl)-1-propylpiperidine, a Potent and Selective
Dopamine D4 Receptor Ligand
Bruno Macchia,a,* Luigi Cervetto,b Gian Carlo Demontis,b Paolo Domiano,c
Biancamaria Longoni,d Marco Macchia,a Filippo Minutolo,a Elisabetta Orlandini,a
Gabriella Ortorea and Chiara Papia
a
Á
Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Italy
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Universita di Pisa, Italy
b
Á
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Universita di Parma, Italy
c
Á
d
Á
Dipartimento di Fisiologia e Biochimica, Universita di Pisa, Italy
Received 1 August 2000; revised 17 October 2000; accepted 6 November 2000
AbstractÐThe synthesis of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine 1, a potent and selective D4 dopa-
minergic ligand, was performed. The 3-(3,4-dimethylphenyl)-1-propylpiperidine with the R con®guration showed an anity for the
D4 receptors 6-fold higher than the corresponding enantiomer with the S con®guration. Furthermore, the (R)-1 enantiomer proved
to be highly selective for D4 receptors with respect to D2±D3 receptors, with a Ki ratio higher than 25,000, while the (S)-1 enan-
tiomer was about 100-fold less selective than the (R)-1 one # 2001 Elsevier Science Ltd. All rights reserved.
Cerebral dopaminergic receptors have been classi®ed into
D1-like and D2-like subtypes according to biochemical
criteria.1 D2-like receptors are the target of classic anti-
psychotics, which are used in the therapy of schizophrenic
syndromes. However, serious adverse e€ects are asso-
ciated with antipsychotic therapy, including extra-
pyramidal Parkinson-like syndromes.2 Several isoforms
of D2-like receptors, which are the D2, D3 and D4 sub-
types, have been identi®ed by means of cloning techni-
ques.3 The D2 isoform is predominant in most brain
areas. At the level of the striatum (believed to be the ori-
gin of extrapyramidal disturbances), the D3 isoform is
also expressed, whereas D4 receptors are present in sig-
ni®cant quantities in the cortex and other areas that con-
trol emotional and cognitive functions.4 Therefore, it has
been hypothesised that D4 selectivity might be a pharma-
cological requisite in order to obtain antipsychotic drugs
devoid of side-e€ects, or at least possessing limited side-
e€ects, as observed for clozapine.5 Furthermore, recent
neurophysiological studies have revealed a possible cor-
relation between a decrease, due to ageing, in the den-
sity of cerebral dopaminergic receptors (D2-like?) and a
loss of the capacity for coordination and for mental
agility, which is typical of various neurodegenerative
syndromes.6 The possibility of making use of drugs with
a high degree of selectivity at the level of the dopamine
D4 receptor subtype might thus be extremely useful in
the study of the physiology and pathology of important
higher brain functions.
3-Phenylpiperidines (PPEs) have been studied for several
years in view of their dopaminergic properties and pre-
clamol (3-PPP), a 3-(3-hydroxyphenyl)-1-propylpiper-
idine, has been reported to be the ®rst autoreceptor-
selective agonist.7 It has recently been discovered by us
that a dimethyl substitution on the phenyl ring of PPEs
a€ords compounds with a marked anity towards D4
receptors,8 particularly in the case of 1, which proved to be
the most potent and selective compound for D4 receptors.8
In order to verify whether the chirality present in PPE 1
could be a prerequisite for its biological activity, the
synthesis of the two enantiomers of PPE 1 [(S)-1, (R)-1]
*Corresponding author. Fax: +39-50-40517; e-mail: bmacchia@
farm.unipi.it
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00633-8

224
B. Macchia et al. / Bioorg. Med. Chem. Lett. 11 (2001) 223±226
Scheme 1. Reagents and conditions: (i) (R)-( )-a-methoxyphenylacetic acid (1 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (1.2 equiv), 1-hydroxybenzotriazole (1.5 equiv), anhyd THF, rt, 24 h; (ii) potassium tert-butoxide (5 equiv), THF, H2O, rt, 24 h; (iii) propio-
naldehyde (2.4 equiv), sodium cyanoborohydride (2.1 equiv), MeOH, rt, 24 h.
was performed. The anities of enantiomers (S)-1 and
(R)-1 towards dopamine receptor subtypes is discussed
and compared with those shown by chiral (S)- and (R)-
3-PPP.
Chemistry
Racemic 3-(3,4-dimethylphenyl)piperidine 28 (Scheme 1)
was treated with (R)-( )-a-methoxyphenylacetic acid, in
the presence of 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride and 1-hydroxybenzotriazole, to
give a diastereoisomeric mixture of amides (S,R)-3 and
(R,R)-3; diastereoisomers (S,R)-3 and (R,R)-3 were
separated by column chromatography9 and then hydro-
lysed to the corresponding enantiomerically pure 3-(3,4-
Figure 1. ORTEP 2 plot (50% probability level for thermal ellipsoids)
of the X-ray structure of (R,R)-3, showing the crystallographic atom
numbering scheme.
dimethylphenyl)piperidines (S)-2 and (R)-2, by reaction
with potassium tert-butoxide.10 Reductive alkylation of
piperidines (S)-2 and (R)-2 with propionaldehyde and
sodium cyanoborohydride yielded enantiomerically
pure 3-(3,4-dimethylphenyl)-1-propylpiperidines (S)-1
and (R)-1.11
showed that the two chiral centres both possess an R
con®guration. On this basis, it was then possible to assign
the proper stereochemistry of the diastereoisomeric amide
(S,R)-3 and also of piperidines (S)-2, (R)-2 and (S)-1, (R)-
1, bearing in mind that in the synthetic sequence leading
from (S,R)-3 and (R,R)-3 to (S)-1 and (R)-1, the chiral
centres were not involved.
The structures and con®gurations of the intermediate
compounds (S,R)-3, (R,R)-3, (S)-2, (R)-2 and of the
®nal products (S)-1 and (R)-1 were assigned on the basis
However, in order to con®rm unequivocally the lack of
racemisation during the hydrolysis reaction of amides
(S,R)-3 and (R,R)-3 to give, respectively, the 3-(3,4-
dimethylphenyl)piperidines (S)-2 and (R)-2, the piper-
idine (R)-2 was treated with (R)-( )-a-methoxy-
phenylacetic acid following the same procedure used in
1
of a comparison of the H NMR spectral data of all
compounds9 11 and a crystallographic analysis of one of
the diastereoisomeric amides [(R,R)-3].12 An ORTEP
plot of the X-ray structure of (R,R)-3 (see Figure 1),
reporting the crystallographic atom numbering scheme,

B. Macchia et al. / Bioorg. Med. Chem. Lett. 11 (2001) 223±226
Table 1. Binding anities for D1-like and D2-like dopamine receptors
225
KiÆSEM (nM)a
D2±D3 (striatum)c
Compound
D1 (retina)b
D4 (retina)c
(D2±D3)/D4
(R)-1
(S)-1
1
(R)-3-PPP
(S)-3-PPP
Dopamine
( )-Quinpirole
PD 168,077
>100,000
>100,000
>100,000
nd
>100,000
5000Æ2000
11,000Æ4000
404Æ188
8Æ2
4Æ2
23Æ5
>25,000
217
1100
1.02
0.06
9
10Æ2
397Æ201
187Æ88
15Æ6
nd
4 300Æ1200
130Æ25
ndd
nd
241Æ17
59Æ11
25Æ8e
5
732
18,300Æ3600e
aValues represent the means of three to ®ve experiments for each compoundÆstandard error.
bD1-like receptors labelled with [3H]SCH23390.
cD2 D3 and D4 receptors labelled with [3H]YM-09-151-2.
dNot determined.
ePD 168,077 anity for cloned human D2 and D4 receptors were 3740 and 9 nM, respectively.13
1
the case of the racemate 2 (see above). H NMR analy-
sis of the resulting product showed the presence only of
the corresponding diastereoisomer (R,R)-3 (GC, 99%),
without any appreciable quantity of (S,R)-3.
receptor, as indicated by the fact that both enantiomers
proved to possess a signi®cant anity for this receptor,
even if the (R) enantiomer was slightly better than the
(S) one. On the contrary, the di€erent chirality seems to
play an important role in determining a marked value of
selectivity for D4 over D2±D3 receptors, as shown by
the Ki ratio values which are >25,000 and 217, respec-
tively for the (R) and (S) enantiomers.
Results and Discussion
The anities of enantiomers (R)-1 and (S)-1 for D1, and
D2±D3 and D4 isoforms of D2-like receptors were inves-
tigated by binding experiments which were performed as
previously described.8 The results are summarised in
Table 1, together with those obtained for (R)- and (S)-3-
PPP, the endogenous agonist dopamine, the D2-like
selective agonist ( )-quinpirole and the D4-selective
agonist PD 168,077, taken as reference drugs. Data are
expressed as inhibition constant (Ki) values (nM).
References and Notes
1. Kebabian, J. W.; Calne, D. B. Nature 1979, 277, 93.
2. Hornykiewicz, O. Pharmacol. Res. 1966, 18, 925.
3. Gincrich, J. A.; Caron, M. G. Ann. Rev. Neurosci. 1993, 16,
299.
4. Goldman-Rakic, P. S. Ann. Rev. Neurosci. 1988, 11, 137.
5. Van Tol, H. H.; Bunzow, J. R.; Guan, H. C.; Sunahara,
R. K.; Seeman, P.; Niznik, H. B.; Civelli, O. Nature 1991, 350,
610.
6. Volkow, N. D.; Gur, R. C.; Wang, G. J.; Fowler, J. S.;
Moberg, P. J.; Ding, Y. S.; Hitzemann, R.; Smith, G.; Logan,
J. Am. J. Psychiatry 1998, 155, 344.
7. Wikstrom, H.; Sanchez, D.; Lindberg, P.; Hacksell, U.;
Arvidsson, L. E.; Johansson, A. M.; Thorberg, S. O.; Nilsson,
J. L. G.; Svensson, K.; Hjoth, S.; Clark, D.; Carlsson, A. J.
Med. Chem. 1984, 27, 1030.
Both enantiomeric 3-(3,4-dimethylphenyl)-1-propylpi-
peridines (R)-1 and (S)-1 possessed a low anity for D1
receptors. As regards D4 receptors, the 3-(3,4-dimethyl-
phenyl)-1-propylpiperidine with the R con®guration,
(R)-1, showed an anity for D4 receptors 6-fold higher
than the corresponding enantiomer with the S con®g-
uration, (S)-1. As for D2±D3 receptors, the (R)-1 and
(S)-1 enantiomers showed decidedly lower anities than
for D4 receptors and, in this case, (S)-1 proved to be the
preferred one, with a Ki value of 5 mM against a Ki value
higher than 100 mM for (R)-1.
8. Cervetto, L.; Demontis, G. C.; Giannaccini, G.; Longoni,
B.; Macchia, B.; Macchia, M.; Martinelli, A.; Orlandini, E. J.
Med. Chem. 1998, 41, 4933.
9. The resulting diastereoisomeric mixture was puri®ed by
column chromatography (230±400 mesh silica gel, Merck),
eluting with Et2O to give diastereoisomers (S,R)-3 and (R,R)-3
with a purity, respectively, of 80% and 86% (GC). The dia-
stereoisomer (S,R)-3 was further puri®ed (99%, GC) by column
chromatography (230±400 mesh silica gel, Merck), eluting
with diisopropyl ether (180 mg, yield 12%). The diastereo-
isomer (R,R)-3 was obtained practically pure (98%, GC) by
further crystallisation with hexane (440 mg, yield 29%). (S,R)-
These results show that the (R)-1 enantiomer proved to
be highly selective for D4 receptors with respect to D2±
D3 receptors, with a Ki ratio higher than 25,000, while
the (S)-1 enantiomer showed an approximately 100-fold
lower selectivity than (R)-1.
In contrast, it is interesting to note that the R enantiomer
of 3-PPP appeared to lack any selectivity between D4
and D2±D3 receptor isoforms, similar to the S enantio-
mer, whose selectivity was modest.
1
3: H NMR (DMSO-d6, 200 MHz) d 1.18±1.81 (m, 4H), 2.14±
2.18 (m, 6H), 3.18±3.41 (m, 3H), 3.82±4.11 (m, 1H), 4.28±4.57
(m, 1H), 5.13±5.19 (m, 1H), 6.60±6.73 (m, 1H), 6.88±7.03 (m,
2H), 7.28±7.45 (m, 5H). Anal. (C22H27NO2) C, H, N. MS m/e
1
337 (M+). (R,R)-3: H NMR (DMSO-d6, 200 MHz) d 1.11±
1.98 (m, 4H), 2.14±2.18 (m, 6H), 2.38±2.97 (m, 3H), 3.21±3.40
(m, 3H), 3.75±4.18 (m, 1H), 4.29±4.57 (m, 1H), 5.15±5.22 (m,
1H), 6.57±6.70 (m, 1H), 6.88±7.10 (m, 2H), 7.23±7.44 (m, 5H).
Anal. (C22H27NO2) C, H, N. MS m/e 337 (M+).
Conclusions
The chirality present in PPE 1 does not represent an
essential prerequisite for its interaction with the D4

226
B. Macchia et al. / Bioorg. Med. Chem. Lett. 11 (2001) 223±226
10. The solvent was evaporated and the resulting residue was
extracted with Et2O. The organic phase was evaporated to
give a crude residue which was dissolved in EtOH and then
acidi®ed to pH 3 at 0 ꢀC by addition of a saturated Et2O/HCl
solution. Evaporation of the organic solvent gave the appro-
priate crude (S)-2 and (R)-2 as hydrochloride salts which were
Siemens AED di€ractometer, equipped with a Mo Ka source
(using y/2y scan mode, scan speed 3/12 deg min 1, scan width
1.20+0.34 tany, y in the range 3±30 deg) was used to obtain
intensity data and orthorhombic cell parameters: a=10.477(4)
A, b=21.844(3) A, c=8.297(2) A a=b=g=90.0(0) deg, Z=
4, V=1898.9(9) A3, dc=1.18 g cm 3, space group P212121. The
structure was solved by direct methods using SIR97 and
re®ned using SHELX97 by full matrix least squares on Fo
with anisotropic thermal parameters (isotropic for the hydro-
gens). The ®nal R indexes were, respectively: R1=0.0495 for
1045 re¯ections with Fo>4s (Fo), R2=0.1304 for all the 3145
re¯ections, wR2=0.1240. Crystallographic data (excluding
structure factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC 150952.
.
puri®ed by crystallisation with EtOH/Et2O. (S)-2 HCl: yield
.
40%, [a]D=+10.5 (c=0.90, MeOH). (R)-2 HCl: yield 32%,
1
[a]D= 9.9 (c=0.91, MeOH). H NMR spectral data for (S)-
.
2 HCl and (R)-2 HCl were practically identical to their corre-
.
8
.
sponding racemate 2 HCl.
11. The work up was the same as in the case of racemate
8
.
.
1 HCl. (S)-1 HCl: yield 39%, [a]D= 9.7 (c=0.94, MeOH).
(R)-1 HCl: yield 32%, [a]D=+10.0 (c=0.96, MeOH). 1H
.
.
NMR spectral data for (S)-1 HCl and (R)-1 HCl were practi-
.
8
.
cally identical to their corresponding racemate 1 HCl.
13. Glase, S. A.; Akunne, H. C.; Georgic, L. M.; MacKenzie,
R. G.; Manley, P. J.; Pugsley, T. A.; Lawrence, D. W. J. Med.
Chem. 1997, 40, 1771.
12. Crystals of the title compound suitable for X-ray analysis
were obtained by slow evaporation of a hexane solution. A