CGP 12177A modulates brown fat adenylate cyclase activity by interacting with two distinct receptor sites.

The interaction of [(-)-4-(3-t-butylamino-2-hydroxy-propoxy)benzimidazol-2-one] (CGP 12177) (CGP) with receptors that couple to adenylate cyclase was examined in membrane homogenates from rat interscapular brown adipose tissue (IBAT). Although typically regarded as a beta adrenoceptor antagonist, CGP stimulated adenylate cyclase activity with an activation constant of about 3 microM. Consistent with its classification as an antagonist, CGP inhibited norepinephrine-stimulated cyclase activity and did so at concentrations that had little or no stimulatory effect. CGP also inhibited activity stimulated by the atypical agonist [(R*,R*)-4-[2-[[2[(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]phenyl]phenoxyacetic acid (BRL 37344), but only at CGP concentrations that stimulated activity when tested alone. The beta-1-selective antagonist ICI 89,406 blocked norepinephrine-stimulated adenylate cyclase activity, but did not inhibit the activity stimulated by CGP. Together, these results indicate that CGP modulates IBAT adenylate cyclase by interacting with two receptors. One is the beta-1 receptor of which CGP is a high-affinity antagonist. The second appears to be an atypical receptor of which CGP is a partial agonist.