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The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse.

ABSTRACT: Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of ?(9)-tetrahydrocannabinol (?(9)-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of ?(9)-tetrahydrocannabinol (?(9)-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of ?(9)-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to ?(9)-THC, JWH-018, and SDB-001.

SUBMITTER: Banister SD

PROVIDER: S-EPMC3715837 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse.

Banister Samuel D SD Wilkinson Shane M SM Longworth Mitchell M Stuart Jordyn J Apetz Nadine N English Katrina K Brooker Lance L Goebel Catrin C Hibbs David E DE Glass Michelle M Connor Mark M McGregor Iain S IS Kassiou Michael M

ACS chemical neuroscience 20130417 7

Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure-activity relationships within ...[more]

PMID: 23551277

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The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse.

Publications

The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse.

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