title: cis-4-amino-L-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues: part 2.
abstract: Recently, we reported synthesis and activity of a constrained cyclic analogue of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH(2)) and related linear models containing the cis-4-amino-L-proline (cAmp) in place of native Pro(2). In the present article, the adopted rationale is the possible modulation of the receptor affinity of the cAmp containing EM-2 analogues by assigning a different stereochemistry to the Phe(3) and Phe(4) residues present in the ring. Thus, eight more analogues with different absolute configuration at the chiral center of the aromatic residues in positions 3 and 4 have been synthesized and their opioid activity examined. The stereochemical change at the α-carbon atoms leads to a meaningful enhancement of the affinity and activity toward μ opioid receptors with respect to the prototype compound 9: e.g., 9a, K(i)(μ) = 63 nM, GPI (IC(50)) = 480 nM; 9b, K(i)(μ) = 38 nM, GPI (IC(50)) = 330 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: 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; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; 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; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; C105294:endomorphin 2; D011392:Proline