In this study, the ability of a series of dynorphin peptides to inhibit adenylyl cyclase (AC) activity was determined. The endogenous ligand of the kappa opioid receptor, dynorphin A(l-17) (Dyn A(l-17)), produced a significant concentration-dependent inhibition of AC activity in membranes prepared from the caudate putamen (CPu) of naive Fischer 344 rats. The opioid receptor antagonist, naloxone (10(-5)M), which is predominantly mu opioid receptor directed, but with modest kappa and delta receptor activity, partially blocked this inhibition. Nor-Binaltorphimine (10(-5)M), the selective kappa receptor antagonist, also blocked the effect of Dyn A(l-17), but to a lesser degree. [Des-Tyr1]Dyn A(2-17), a major nonopioid biotransformation product of Dyn A(l-17) with known biological activities, also inhibited AC in rat CPu membranes. Dyn A(l-13) inhibited AC, as did its major opioid biotransformation product, Dyn A(l-12). One of the major nonopioid biotransformation products of Dyn A(l-13), Dyn A(4-12), showed no activity. Dyn A(2-12), another nonopioid product of Dyn A(l-13), showed limited activity. Dyn A(l-6), a minor biotransformation product of both Dyn A(l-17) and Dyn A(l-13), also inhibited AC activity. These findings suggest that, in rat CPu membranes, the inhibition of AC activity by Dyn A(l-17) is mediated in part by kappa and mu opioid receptors. In addition, Dyn A(2-17), and to a lesser extent Dyn A(2-12), may bind to a yet unidentified site that is also coupled to the AC enzyme in rat CPU.