O-823

Synthetic sequences were developed for the syntheses of various Δ⁸-THC analogs with either a rigid acetylenic linkage or a cis-double bond in different positions in the side chain.Various alkyne and cis-ene-Δ⁸-THC analogs were also synthesized carrying a functional group such as a cyano, isothiocyano, azido, amino, nitro, bromo, hydroxy, fluoro and a methoxy group at the chain terminal.The in vitro and in vivo pharmacol. of these unique analogs have provided several ligands which are partial agonists or antagonists of the cannabinoid receptor CB1.The 2'-position in the side chain was found to be optimum for activity.

Structure-activity relation studies have established that the alkyl side chain 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 interaction of THC with its receptors.Therefore, a series of analogs with structurally restrained side chains of varying length was synthesized and evaluated for pharmacol. potency in mice and for receptor affinity.The introduction of cis double bonds inserted rigid angles, whereas triple bonds developed regions of planarity.Receptor affinity for the acetylenic and saturated side chains were the same, whereas double bond substitution increased affinity 10-fold.Moreover, the relation between receptor affinity and potency was 10-fold less than that of Δ⁸-THC in the case of some acetylenic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio.Addnl., an acetylene at C2-C3 in the octyl and nonyl side chains favored antinociception by as much as 70-fold.Surprisingly, several high-affinity acetylenic derivatives, especially those with cyano substitutions at the terminus of the side chain, were partial agonists or were inactive.Some of these low-efficacy, high-affinity ligands elicited antagonistic activity.The finding that manipulations of the side chain produces high-affinity ligands with either antagonist, partial agonist, or full agonist effects reveals a critical structural feature for receptor activation.