Novel Adamantyl Cannabinoids as CB1 Receptor Probes

Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2013; 56(10). DOI: 10.1021/jm4000775
Source: PubMed


In previous studies compound 1 (AM411), a 3-(1-adamantyl) analog of the phytocannabinoid (-)-∆(8)-tetrahydrocannabinol (∆(8)-THC) was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of the 1-adamantyl group at the C-3 position in a series of tricyclic cannabinoid analogs modified at the 9-northern aliphatic hydroxyl (NAH) position. Of these, 9-hydroxymethyl hexahydrocannabinol 11 (AM4054) exhibited high CB1 affinity and full agonist profile. In the cAMP assay, the 11-hydroxymethyl cannabinol analog 24 (AM4089) had a partial agonist profile, with high affinity and moderate selectivity for rCB1 over hCB2. In vivo results in rat models of hypothermia and analgesia were congruent with in vitro data. Our in vivo data indicates that 3-(1-adamantyl) substitution, within NAH cannabinergics, imparts improved pharmacological profiles when compared to the corresponding, traditionally used, 3-dimethylheptyl analogs and identifies 11 and 24 as a potential useful in vivo CB1 cannabinergic probes.

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