Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists

Citation
Br. Martin et al., Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists, J PHARM EXP, 290(3), 1999, pp. 1065-1079
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
290
Issue
3
Year of publication
1999
Pages
1065 - 1079
Database
ISI
SICI code
0022-3565(199909)290:3<1065:MOTTSC>2.0.ZU;2-8
Abstract
Structure-activity relation studies have established that the alkyl side ch ain in tetrahydrocannabinol (THC) plays a crucial role in the activation of the cannabinoid receptor. Unfortunately, the flexible nature of this side chain has hampered efforts to elucidate the precise nature of the interacti on of THC with its receptors. Therefore, a series of analogs with structura lly restrained side chains of varying length was synthesized and evaluated for pharmacological potency in mice and for receptor affinity. The introduc tion of cis double bonds inserted rigid angles, whereas triple bonds develo ped regions of planarity. Receptor affinity for the acetylenic and saturate d side chains were the same, whereas double bond substitution increased aff inity 10-fold. Moreover, the relationship between receptor affinity and pot ency was 10-fold less than that of Delta(8)-THC in the case of some acetyle nic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio. Additionally, an acetylene at C2-C3 in the oct yl and nonyl side chains favored antinociception by as much as 70-fold. Sur prisingly, several high-affinity acetylenic derivatives, especially those w ith cyano substitutions at the terminus of the side chain, were partial ago nists or were inactive. Some of these low-efficacy, high-affinity ligands e licited antagonistic activity. The finding that manipulations of the side c hain produces high-affinity ligands with either antagonist, partial agonist , or full agonist effects reveals a critical structural feature for recepto r activation.