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The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse
Two novel adamantane derivatives,
adamantan-1-ylÂ(1-pentyl-1<i>H</i>-indol-3-yl)Âmethanone (AB-001)
and <i>N</i>-(adamtan-1-yl)-1-pentyl-1<i>H</i>-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 CB<sub>1</sub> (EC<sub>50</sub> = 16–43 nM) and CB<sub>2</sub> (EC<sub>50</sub> = 29–216 nM) receptors in vitro using a FLIPR membrane potential
assay, with the exception of SDB-002, which demonstrated partial agonist
activity at CB<sub>2</sub> receptors. The activity of AB-001, AB-002,
and SDB-001 in rats was compared to that of Δ<sup>9</sup>-tetrahydrocannabinol
(Δ<sup>9</sup>-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 Δ<sup>9</sup>-tetrahydrocannabinol (Δ<sup>9</sup>-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 Δ<sup>9</sup>-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 Δ<sup>9</sup>-THC, JWH-018, and SDB-001