A NOVEL CLASS OF POTENT TETRAHYDROCANNABINOLS (THCS) - 2'-YNE-DELTA(8)-THCS AND DELTA(9)-THCS

A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of Delta(9) -THC were synthesized and evaluated in vitro and in vivo activity. Ana logs were evaluated for receptor affinity in a [H-3]CP-55,940 displace ment assay and for in vivo pharmacological activity in a mouse procedu re utilizing a tetrad of measures. These compounds represent a prelimi nary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times grea ter than that observed for Delta(9)-THC. However, the in vivo activiti es of these compounds varied greatly. All analogs proved to possess th e greatest potency for production of antinociception, with activity si milar to or less than that observed for the production of hypomotility , hypothermia, and catalepsy. The most potent analog 11b exhibited an ED(50) of 0.031 mg/kg in the tail-flick procedure, with values in othe r measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a K-I of 11 nM. exhibited ED(50) values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as we ll as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor ac tivity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagoni st properties (at least for immobility and activity measures). It is u nclear why these acetylenic analogs were so potent in vitro, while onl y one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for Delta(9)-THC. It is possible these side chain modifications do not interfere with receptor recognition, but li mit receptor activation or second messenger signal transduction. Regar dless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.