Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents.

Abstract

Opening of the pyran ring of delta 9-tetrahydrocannabinol (THC) produces cannabidiol, a bicyclic cannabinoid devoid of many pharmacological properties produced by delta 8-THC or delta 9-THC. Interestingly, the bicyclic compound CP-47,497 (VI) has been described as producing many of the pharmacological effects produced by delta 9-THC, and another related bicyclic analog CP-55,940 (XIV) has been used to successfully define a cannabinoid binding site. A series of 16 bicyclic analogs of VI and XIV were evaluated and compared with the pharmacological profile of cannabidiol, delta 8-THC and delta 9-THC. The goals of the studies described herein were to determine whether these bicyclic analogs possess similar pharmacological properties of delta 9-THC, to compare pharmacological activity after s.c. and i.v. administration, and to evaluate the structure-activity relationship of this series of analogs for further insight into cannabinoid mechanism of action. Each analog was evaluated for its ability to produce hypoactivity, hypothermia, antinociception and catalepsy in mice. The ED50 values generated from these assays were averaged to provide an index of activity. The ED50 values for delta 9-THC varied from 1.0 to 1.5 mg/kg, giving an overall index of activity of 1.3. The index for delta 8-THC was 6.0, making this isomer 4-fold less potent. Although several bicyclic analogs (V, VI, VII, VIII, XI, XII, XIV and XVI) proved to be truly cannabimimetic, three (IV, IX and X) were sufficiently unique to be classified as noncannabimimetic. The index of activity of cannabimimetic bicyclic analogs varied from 0.2 to 2.2, although some minor differences between the bicyclics and delta 9-THC exist.(ABSTRACT TRUNCATED AT 250 WORDS)