title: The cis-4-amino-L-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues.
abstract: Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH(2)) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro(2) represents a crucial factor for the ligand structural and conformational properties. Proline is in fact an efficient stereochemical spacer, capable of inducing favorable spatial orientation of aromatic rings, a key factor for ligand recognition and interaction with receptors. Here the Pro(2) has been replaced by 4(S)-NH(2)-2(S)-proline (cAmp), a proline/GABA cis-chimera residue. This bivalent amino acid maintains the capacity to influenc the tetrapeptide conformation and offers the opportunity to generate new linear models and unusually constrained cyclic analogues characterized by an N-terminal Tyr bearing a free α-amino group. The results indicate that the new analogues do not show affinity for both δ and κ opioid receptors and bind only poorly to the μ receptors (for cyclopeptide 9: K(i)(μ) = 660 nM; GPI (IC(50)) = 1.4% at 1 μM; for linear tetrapeptide acid 13: K(i)(μ) = 2000 nM; GPI (IC(50)) = 0% at 1 μM; for linear tetrapeptide amide 15: K(i)(μ) = 310 nM; GPI (IC(50)) = 894 nM).
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Chieti-Pescara G. d'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy. a.mollica@unich.it
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.forename: Azzurra
authors.initials: A
authors.lastname: Stefanucci
authors.forename: Federica
authors.initials: F
authors.lastname: Feliciani
authors.forename: Cristina
authors.initials: C
authors.lastname: Campestre
authors.forename: Luisa
authors.initials: L
authors.lastname: Mannina
authors.forename: Anatoly P
authors.initials: AP
authors.lastname: Sobolev
authors.forename: Gino
authors.initials: G
authors.lastname: Lucente
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Shou-Wu
authors.initials: SW
authors.lastname: Ma
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D011392:Proline