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
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.