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. 2004 Dec 1;6(4):23–35. doi: 10.1208/aapsj060430

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

Spyros P Nikas 1, Jolanta Grzybowska 1, Demetris P Papahatjis 2, Avgui Charalambous 1, Ali R Banijamali 1,3, Ravi Chari 1, Pusheng Fan 1, Therapia Kourouli 2, Sonyuan Lin 1, Albert J Nitowski 3, Gilbert Marciniak 1, Yan Guo 1, Xiuyan Li 1, Chia-Lin J Wang 4, Alexandros Makriyannis 1,✉
PMCID: PMC2751226  PMID: 15760095

Abstract

The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (−)-Δ8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects. Conversely, 2-iodo substitution on the phenolic ring leads to a 2-fold reduction in affinity while iodo-substitution in the C1'-position of the side chain lowers the compound's affinity for CB1 by more than 8-fold. The pharmacophoric requirements resulting from halogen-substitution are explored using computer modeling methods.

Keywords: tetrahydrocannabinol, halogen substitution, CB1 cannabinoid receptors

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