title: Nonpeptide/peptide chimeric ligands for the nociceptin/orphanin FQ receptor: design, synthesis and in vitro pharmacological activity.
abstract: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the G-protein coupled receptor referred to as N/OFQ peptide (NOP) receptor. NOP receptor activation by N/OFQ modulates several biological functions both at central and peripheral level. Structure activity relationship (SAR) studies demonstrated that the N/OFQ sequence can be divided into a N-terminal tetrapeptide 'message' crucial for receptor activation and a C-terminal 'address' important for receptor binding. On the basis of this message/address concept we synthesized some chimeric compounds in which we substituted the natural message domain with the nonselective nonpeptide NOP ligand (8-Naphthalen-1-yl-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4,5]dec-3-yl)-aceticacid methyl ester (NNC 63-0532) and used as address domain the peptide sequences Thr-NH2, N/OFQ(5-9)-NH2, N/OFQ(5-13)-NH2 and N/OFQ(5-17)-NH2. All the compounds were pharmacologically evaluated in the electrically stimulated guinea-pig ileum. NNC 63-0532 produced a concentration-dependent inhibition of the electrically induced twitches showing, in comparison with N/OFQ, lower potency and higher maximal effects. In addition, contrary to N/OFQ, the effects of NNC 63-0532 were insensitive to the NOP selective antagonist [Nphe1, Arg14, Lys15]N/OFQ-NH2 (UFP-101) while prevented by naloxone. Similar results were obtained with NNC 63-0532/Thr-NH2 and NNC 63-0532/N/OFQ(1-9)-NH2. On the contrary, the inhibitory effects of NNC 63-0532/N/OFQ(5-13)-NH2 and NNC 63-0532/N/OFQ(5-17)-NH2 were slightly antagonized by UFP-101 while naloxone prevented the effects of the high but not of the low concentrations of the two ligands. These data indicate that it is possible to functionalize with the N/OFQ address sequence a nonpeptide NOP ligand for increasing its binding to the NOP receptor. Moreover, these results corroborate the idea that the 5-13 sequence represents the crucial core of the N/OFQ address domain.
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: G
authors.initials: G
authors.lastname: Carra'
authors.forename: G
authors.initials: G
authors.lastname: Calo'
authors.forename: C
authors.initials: C
authors.lastname: Trapella
authors.forename: E
authors.initials: E
authors.lastname: Marzola
authors.forename: D
authors.initials: D
authors.lastname: Rizzi
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009270:Naloxone / Q000737:chemistry / Q000494:pharmacology; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000085:Acetates; D008024:Ligands; D009270:Naloxone; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C417686:(8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro(4.5)-dec-3-yl)acetic acid methyl ester; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C466980:nociceptin orphanin FQ(1-17)OH