STRUCTURES THAT DELINEATE ORPHANIN FQ AND DYNORPHIN-A PHARMACOLOGICALSELECTIVITIES

Strict pharmacological selectivity in families of structurally related ligands and receptors may result from a key process in evolution aimi ng at increasing diversity in neurotransmission. An intriguing example of such exclusive specificity can be found in the newly discovered or phanin FQ (OFQ) system when it is compared with the opioid system, Bot h OFQ and its receptor share a high degree of sequence similarity to t he opioid peptides and their corresponding receptors, respectively, Ho wever, OFQ does not activate opioid receptors, nor do the opioid pepti des elicit biological activity at the OFQ receptor, We have therefore investigated the basis for the inherent selectivity of the primary str uctures of OFQ and dynorphin A, its closest counterpart, A series of t runcated and/or chimeric peptides led to the conclusion that both pept ides contain domains which establish their pharmacological selectivity , In the OFQ molecule we could delineate a domain that prevents its ab ility to activate the kappa-opioid receptor by apparently repelling it s binding. In both peptides the selectivity-generating domains are com posed of single residues in key positions together with short stretche s of amino acids which do not overlap. To prove this concept, we desig ned a universal agonist and found it active at both the OFQ receptor a nd the kappa-opioid receptor, Our observations suggest that a coordina ted mechanism of evolution has separated the orphanin FQ system from t he opioid system.