The abilities of lipophilic
cannabinoid drugs to regulate
adenylate cyclase activity in
neuroblastoma cell membranes were analyzed by thermodynamic studies. Arrhenius plots of
hormone-stimulated
adenylate cyclase activity exhibited a break point at 20 degrees. The break point was reduced to 14 degrees by
benzyl alcohol, consistent with results from other laboratories that have correlated this response with the increase in membrane fluidity induced by
benzyl alcohol. Because
cannabinoid drugs partition into
membrane lipids and alter membrane fluidity parameters in a number of model systems, it was of interest to examine the influence of delta 9-tetrahydrocannabinol and
cannabidiol on
enzyme activity analyzed by the Arrhenius plot. delta 9-Tetrahydrocannabinol, known to inhibit
adenylate cyclase, failed to decrease the transition temperature either at 1 microM or at concentrations exceeding its aqueous solubility (30 microM), suggesting that delta 9-tetrahydrocannabinol could not mimic the effects observed with
benzyl alcohol. In contrast, 30 microM
cannabidiol, which stimulated
enzyme activity slightly, decreased the Arrhenius plot break point to 17.5 degrees. The decrease in the transition temperature in response to
benzyl alcohol or
cannabidiol was not accompanied by a change in activation energies above or below the transition temperature. delta 9-Tetrahydrocannabinol inhibits
adenylate cyclase activity via Gi as does the
muscarinic agonist carbachol (Howlett et al., Mol Pharmacol 29: 307-313, 1986). Both
carbachol and delta 9-tetrahydrocannabinol decreased the enthalpy and entropy of activation. The net free energy of activation at 37 degrees was increased in the presence of both of these inhibitory agonists. These data suggest that, for the entropy-driven
hormone-stimulated
adenylate cyclase enzyme, less disorder of the system occurs in the presence of regulators that inhibit the
enzyme via Gi. In summary, thermodynamic data suggest that
cannabidiol can influence
adenylate cyclase by increasing membrane fluidity, but that the inhibition of
adenylate cyclase by delta 9-tetrahydrocannabinol is not related to membrane fluidization.