PHARMACOLOGICAL CHARACTERIZATION OF 3 NOVEL CANNABINOID RECEPTOR AGONISTS IN THE MOUSE ISOLATED VAS-DEFERENS

The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl -3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole, produced a dose-related inhibition of electrically evoked contractions of the mo use vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM resp ectively. K-d values of the selective CB1 cannabinoid receptor antagon ist, SR141716A 1-yl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide hydr ochloride], determined in the vas deferens from experiments with these compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating t heir susceptibility to antagonism by SR141716A is similar to that of t heir parent compound, the CB, cannabinoid receptor agonist WIN 55,212- 2 ,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone}. SR141716A (100 nM ) had no effect on the actions of two non-cannabinoid receptor agonist s, morphine and clonidine. These results provide strong support for th e hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3( 1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are cannabinoid receptor agonists and confirm that the WIN 55,212-2 molecule can be m odified considerably without detectable loss of cannabinoid activity.