Structures That Delineate Orphanin FQ and Dynorphin A Pharmacological Selectivities

Abstract

Strict pharmacological selectivity in families of structurally related ligands and receptors may result from a key process in evolution aiming at increasing diversity in neurotransmission. An intriguing example of such exclusive specificity can be found in the newly discovered orphanin FQ (OFQ) system when it is compared with the opioid system. Both OFQ and its receptor share a high degree of sequence similarity to the opioid peptides and their corresponding receptors, respectively. However, OFQ does not activate opioid receptors, nor do the opioid peptides elicit biological activity at the OFQ receptor. We have therefore investigated the basis for the inherent selectivity of the primary structures of OFQ and dynorphin A, its closest counterpart. A series of truncated and/or chimeric peptides led to the conclusion that both peptides contain domains which establish their pharmacological selectivity. In the OFQ molecule we could delineate a domain that prevents its ability to activate the -opioid receptor by apparently repelling its binding. In both peptides the selectivity-generating domains are composed of single residues in key positions together with short stretches of amino acids which do not overlap. To prove this concept, we designed a universal agonist and found it active at both the OFQ receptor and the -opioid receptor. Our observations suggest that a coordinated mechanism of evolution has separated the orphanin FQ system from the opioid system.

Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats

“…The N/OFQ peptide binds with high affinity the opioid receptor-like 1 (ORL1) receptor, recently included in the opioid receptor family and renamed NOP, whereas it does not activate the classical opioid receptors (μ, κ, and δ). At the intracellular level, however, the activation of membrane NOP receptors exerts actions similar to those induced by activation of the other opioid receptors, namely, inhibition of cAMP production, closure of voltage-sensitive Ca ++ channels and enhancement of an outward K + conductance (Meunier et al 1995;Reinscheid et al 1995Reinscheid et al , 1998. Nevertheless, naloxone, a non-selective opioid antagonist, does not block N/OFQ intracellular events (Henderson and McKnight 1997;Darland et al 1998), confirming that the pharmacological actions of this peptide are not mediated by the classic opioid receptors.…”

“…Nociceptin (N/OFQ), also referred to as orphanin FQ, is a 17-aminoacid peptide that shows structural homology with opioid peptides, particularly with dynorphin A, but is lacking the N-terminal tyrosine necessary for activation of traditional opioid receptors (Meunier et al 1995;Reinscheid et al 1995Reinscheid et al , 1998. The N/OFQ peptide binds with high affinity the opioid receptor-like 1 (ORL1) receptor, recently included in the opioid receptor family and renamed NOP, whereas it does not activate the classical opioid receptors (μ, κ, and δ).…”

Release of orphanin FQ/nociceptin in the medial preoptic nucleus and ventromedial nucleus of the hypothalamus facilitates lordosis

“…However, NOP exhibits little affinity for binding endogenous classical opioid ligands (endorphins, enkephalins, and dynorphins) and is not affected by naloxone antagonism, a hallmark of classic opioid receptors (Fukuda, Kato, Mori, Nishi, Takeshima, Iwabe, Miyata, Houtani, and Sugimoto, 1994;Lachowicz et al, 1995;Lee, Nicholson, and McKnight, 1997;Mollereau et al, 1994;Pfaus and Pfaff, 1992;Wang et al, 1994). The only known endogenous ligand for NOP is OFQ/N, which is similar in structure to dynorphin A, a KOP endogenous ligand (Meunier, 1997;Meunier, Mollereau, Toll, Suaudeau, Moisand, Alvinerie, Butour, Guillemot, Ferrara, Monsarrat, and et al, 1995;Reinscheid, Higelin, Henningsen, Monsma, and Civelli, 1998), but lacks the NH 2 terminal amino acid tyrosine necessary for activation of the MOP, DOP, or KOP receptors. Instead, the NH 2 terminal amino acid of OFQ/N is replaced with a phenylalanine (Meunier, 1997;Meunier et al, 1995;Reinscheid et al, 1998), allowing for specific binding to the NOP receptor (Ardati, Henningsen, Higelin, Reinscheid, Civelli, and Monsma, 1997;Butour, Moisand, Mazarguil, Mollereau, and Meunier, 1997;Dooley and Houghten, 1996;Guerrini, Calo, Rizzi, Bianchi, Lazarus, Salvadori, Temussi, and Regoli, 1997;Reinscheid, Ardati, Monsma, and Civelli, 1996;Shimohigashi, Hatano, Fujita, Nakashima, Nose, Sujaku, Saigo, Shinjo, and Nagahisa, 1996).…”

The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine

“…Furthermore, the endogenous ligand of the ORL-1 receptor, known as orphanin FQ (Reinscheid et al, 1995) or nociceptin (Meunier et al, 1995), a heptadecapeptide, also shows some degree of sequence homology to endogenous opioid peptides, and in particular to dynorphin A (Reinscheid et al, 1998). The ORL-1 receptor and its endogenous ligand are widely distributed throughout the central nervous system (CNS) and particularly in brain regions involved in motivational and emotional behaviors (Neal, Jr. et al, 1999b;Neal, Jr. et al, 1999a).…”