Derivatives of 17-(2-methylallyl)-substituted noroxymorphone: variation of the delta address and its effects on affinity and selectivity for the delta opioid receptor.

Article abstract of DOI:10.1016/S0960-894X(01)00580-7

In an effort to establish the importance of the N-(2-methylallyl) substituent in the noroxymorphone series, several derivatives have been synthesized, retaining that N-substituent and modifying the delta address moiety. A few compounds showed moderate binding affinity and selectivity for the delta receptor; none displayed a pharmacological profile as exceptional as N-(2-methylallyl)noroxymorphindole. A second study showed that 3-O-methylation of all derivatives decreases binding affinity. The present results indicate that only a combination of the N-(2-methylallyl) group and an indole delta address provided high selectivity for the delta receptor.

Full text of DOI:10.1016/S0960-894X(01)00580-7

Bioorganic & Medicinal ChemistryLetters 11 (2001) 2883–2885
Derivatives of 17-(2-Methylallyl)-substituted Noroxymorphone:
Variation of the Delta Address and Its Effects on Affinity and
Selectivity for the Delta Opioid Receptor
Thomas Ullrich,a Christina M. Dersch,b Richard B. Rothman,b
Arthur E. Jacobsona and Kenner C. Ricea,*
aLaboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
bClinical Psychopharmacology Section, NIDA, Addiction Research Center, Baltimore, MD 21224, USA
Received 6 July2001; accepted 15 August 2001
Abstract—In an effort to establish the importance of the N-(2-methylallyl) substituent in the noroxymorphone series, several deri-
vatives have been synthesized, retaining that N-substituent and modifying the d address moiety. A few compounds showed mod-
erate binding affinityand selectivityfor the
d receptor; none displayed a pharmacological profile as exceptional as N-(2-
methylallyl)noroxymorphindole. A second study showed that 3-O-methylation of all derivatives decreases binding affinity. The
present results indicate that onlya combination of the N-(2-methylallyl) group and an indole d address provided high selectivityfor
the d receptor. Published byElsevier Science Ltd.
Naltrindole (NTI, 1)1 (Fig. 1) exhibits veryhigh affinity
for the opioid d-receptor and is moderatelyselective ( m/
d affinityratio=120). Since d antagonists are reported
d address moieties have been studied extensivelyon
NTI.9 We decided to choose representative structures
among a varietyof referenced molecules bearing inter-
esting pharmacological profiles, but also wanted to
provide a broad range of different chemical entities that
can be obtained in onlyone or two steps from the same
starting material. Emphasis was hence laid on rigid
(fused, conjugated or spiro-annulated) carbocycles and
heterocyles. The moieties (E)-benzylidene, spiroindane,
benzofuran and 3-(p-chlorophenyl)pyridine scaffolds
were chosen for their high-affinitybinding and d-selec-
2
to be potentiallyuseful in the treatment of cocaine
abuse,3,4 and in the suppression of tolerance and
dependence,5 there is broad interest in new d receptor
antagonists more selective than NTI. We have recently
reported the development of a new opioid ligand, N-(2-
methylallyl)oxymorphindole (TU753, 2), that exhibits
high affinity, high antagonist potency, and impressively
high selectivityfor the d receptor, proving that minor
modifications of the N-substituent in NTI can lead to a
tivityprofile in the N-cyclopropylmethyl series.9,10
A
6
significantlyaltered profile. Thus, 2 is more selective
pyrazole was also prepared using a (dimethylamino)-
methylene substituent, which will allow the future pre-
paration of other N-heterocycles. The pyrazole moiety,
lacking a necessaryextension into the space that is cru-
cial for the lipophilic d address domain, served for
comparison studies. Since several reactions required
than NTI in binding assays (see Table 1) and as an
antagonist in the GTPgS assayand, as well, in smooth
muscle (MVD/GPI) functional assays (NTI: m/d selec-
tivity=90; 2: m/d selectivity=2200).6,7 In an effort to
establish whether the N-methylallyl substituent was the
determining factor for the biological activityof the
molecule, we synthesized several derivatives of 2 by
modifying the ‘d address’, the part of the molecule that
is considered unique for this subtype and, which func-
tions to enhance the affinityof the ligand without con-
tributing to signal transduction.8
*Corresponding author. Tel.: +1-301-496-1856; fax: +1-301-402-
0589; e-mail: kr21f@nih.gov
Figure 1. Structures of NTI and TU753.
0960-894X/01/$ - see front matter Published byElsevier Science Ltd.
PII: S0960-894X(01)00580-7

2884
T. Ullrich et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2883–2885
protection of the phenolic group (position 3), an O-
methyl series was also synthesized and compared to the
OH compounds.
moderate affinityfor the d receptor was observed in
both benzofuran compounds, 6 (Ki=8.2 nM, m/d=160,
k/d=71), and—to a lesser extent—its methylated deri-
vative, 16 (Ki=44 nM, m/d=140, k/d=230). The latter
had selectivitycomparable to NTI. With the exception
of 15 and 16, all O-methylated compounds showed poor
affinityand/or selectivityfor the d receptor. Compounds
7 and 15 exhibited moderate binding affinityand selec-
tivityfor the d receptor, and the pyrazole derivative 14,
being devoid of a d address moiety, unsurprisingly
showed affinities for all three receptors.
Noroxymorphone (3) was N-alkylated with 3-bromo-2-
methylpropene to afford N-(2-methylallyl)oxymorphone
(4), the starting material for all following conversions
(Scheme 1).
The indole (2), benzofuran (6), pyridine (7), and ben-
zylidene (8) derivatives were prepared as suggested in
the literature.6,10ꢀ12 The spiroindane (15)13 and pyrazole
(14)14 derivatives could not be directlyobtained from 4,
but required phenolic O-protection to give 13, which
was accomplished byintroducing a methyl group that
could be cleaved afterwards with BBr3.14 All other
compounds were O-methylated correspondingly.15 It is
worthyof note that step (iv) in Scheme 1, the pyrazole
synthesis, required employment of allyl alcohol instead
of the methanol used in the referenced literature.14 It
was observed that in the absence of unsaturated
solvents, the hydrazine reagent would reduce the N-
methallyl double bond entirely under the chosen condi-
tions, probablybyformation of a highlyreactive
diimide species. Allyl alcohol was an appropriate sol-
The present studyindicates that, although N-(2-methyl-
allyl)noroxymorphindole has been shown to be more
selective than its N-CPM analogue,6 the N-(2-methyl-
allyl) substituent does not appear to provide the same
selectivityin our molecules with other d address moi-
eties. Rather, binding affinityand selectivityfor the
d
receptor in the investigated compounds decreased
remarkably, with the exception of benzofuran derivative
6, which had a binding affinitysimilar to that of indole
2. Furthermore, the results obtained implythat 3- O-
methylation is detrimental to either or both d affinity
and selectivity. It may be concluded that the unique
16
vent to efficientlyinhibit the reduction, thus allowing
complete conversion to the desired pyrazole (10).
Whereas the indole (5), benzofuran (6), and pyridine (7)
derivatives could be O-methylated easily with TMS-
diazomethane,14 this method was not applicable to the
benzylidene compound (8). Experimental data sug-
gested that the a,b-unsaturated ketone underwent
cycloaddition with diazomethane17 prior to or con-
comitantlywith,
trimethylammonium chloride was used, affording
O-methylation. Instead, phenyl-
methyl derivative 11 in good yield.18
Radioligand binding assays at m, k, and d opioid recep-
tors were performed as previouslydescribed. The affi-
6
nities of all tested substances, as well as those of
compounds 1 and 2, are summarized in Table 1. Thus,
Table 1. Opioid receptor binding affinityand selectivityof NTI ( 1),
TU753 (2) and its d address modified analogues 6–17
Ki (nM) (SEM)
Selectivityratio
ma
db
kc
m/d
k/d
1d
2e
6
7
8
27ꢂ1.3
7900ꢂ820
1300ꢂ40
>6000
0.22ꢂ0.05
4.7ꢂ0.9
8.2ꢂ1.0
16ꢂ1.0
30ꢂ3.6
3800ꢂ220
580ꢂ30
300ꢂ20
4500ꢂ520
>7000
120
1700
160
>380
21
140
810
71
19
21
—
1
>2
>28
1
4500ꢂ320
210ꢂ20
9
>6000
>7200
—
10
11
12
14
15
16
17
>6000
>6000
>6000
140ꢂ9.0
2000ꢂ230
>6000
2400ꢂ200
3400ꢂ290
500ꢂ90
40ꢂ3.0
3100ꢂ220
>2
>1
>12
4
49
140
23
>7000
>14000
38ꢂ3.0
Scheme 1. (i) 3-Bromo-2-methylpropene, NaHCO3, DMF, 80 ꢁC, 2 h,
85%; (ii) TMS–CHN2, Et3N, MeOH/MeCN, 25 ꢁC, 3 h, 93%; (iii)
41ꢂ6.0
1000ꢂ90
>10000
24
230
12
ꢁ
.
44ꢂ5.0
DMF dimethylacetal, 110 C, 6 h, 71%; (iv) H2NNH2 H2O, 2-prope-
nol/H2O, 110 ꢁC, 2 h, 99%; (v) a,a0-dibromo-o-xylene, LiHMDS, 12-
crown-4, THF, ꢀ78!60 ꢁC, 48 h, 55%; (vi) BBr3, CH2Cl2, 0!25 ꢁC,
>6000
260ꢂ30
3200ꢂ350
ꢁ
aDisplacement of [3H]DAMGO.
bDisplacement of [3H]DADLE.
cDisplacement of [3H]U69,593.
dSee ref 19.
3 h, 83%; (vii) PhNHNH2 HCl, MeOH/3 N HCl, 80 C, 12 h, 97%;
.
(viii) PhONH2 HCl, MeSO3H, EtOH, 78 ꢁC, 18 h, 83%; (ix) p-
.
ClC6H4CH(CHO)2, NH4OAc, AcOH, 110 ꢁC, 48 h, 55%; (x) PhCHO,
AcOH/pyrrolidine/toluene, 25 ꢁC, 96 h, 86%; (xi) PhNMe3Cl, K2CO3,
DMF, 80 ꢁC, 2 h, 82%.
eSee ref 6.

T. Ullrich et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2883–2885
2885
pharmacological profile of TU753 (2) results from a
combination of the N-2-methylallyl group and the
indole moiety, and that the absence of either of them
leads to a deterioration of that profile.
(b) Dondio, G.; Ronzoni, S.; Petrillo, P. Exp. Opin. Ther. Pat.
1999, 9, 353.
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15. Note: Elemental analyses were performed on all novel
compounds 6–17 byAtlantic Microlabs Inc., Norcross, GA,
USA, and the obtained results were within ꢂ0.4% of the the-
oretical values. 1H NMR and MS data were also in accord
with the depicted molecular structures, and the compounds
present as hydrochloride salts all showed melting points
>250 ꢁC, respectively.
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