CANNABINOID STRUCTURE-ACTIVITY-RELATIONSHIPS - CORRELATION OF RECEPTOR-BINDING AND INVIVO ACTIVITIES

Although a receptor exists for cannabinoid drugs, it is uncertain whic h pharmacological actions this receptor mediates. This structure-activ ity relationship investigation was initiated to determine which effect s might correspond to binding affinity for the cannabinoid receptor, a s well as to explore the binding requirements of this site. The abilit y of nearly 60 cannabinoids to displace [H-3]CP-55,940 ydroxy-4-(1,1-d imethylhep-tyl)phenyl]-4-[3-hydroxy propyl] cyclohexan-1-ol} was deter mined before establishing correlations between receptor affinity and i n vivo pharmacological potency. Analysis of [H-3]CP-55,940 binding ind icated a Hill coefficient of 0.97, a B(max) of 499 pM (3.3 pmol/mg of protein) and an apparent K(d) of 924 pM. Closer inspection indicated t he binding assay exhibited ''zone B'' characteristics, and use of corr ection equations indicated a true K(d) for CP-55,940 of 675 pM. The st ructure-activity relationship indicated the importance of side chain s tructure to high-affinity binding, with the most potent analogs (K(I) < 10 nM) possessing either a dimethylheptyl side-chain, a similarly co mplex branched side chain or a halogen substituent at the 5' position. Comparative analysis of K(I) values to in vivo potency in a mouse mod el indicated a high degree of correlation between parameters for the d epression of spontaneous locomotor activity (r = 0.91) and for the pro duction of antinociception (r = 0.90), hypothermia (r = 0.89) and cata lepsy (r = 0.85). Similarly high correlations were demonstrated betwee n binding affinity and in vivo potency in both the rat drug discrimina tion model (r = 0.81) and for psychotomimetic activity in humans (r = 0.88). Thus, these studies appear to indicate that the requirements fo r activation of the cannabinoid receptor are similar across different species, and that receptor binding is sufficient to mediate many of th e known pharmacological effects of cannabinoids.