Synthesis and evaluation of new endomorphin-2 analogues containing (Z)-alpha,beta-didehydrophenylalanine (Delta(Z)Phe) residues.
New endomorphin-2 (EM-2) analogues incorporating (Z)-alpha,beta-didehydrophenylalanine (Delta(Z)Phe) in place of the native phenylalanine in EM-2 are reported. Tyr-Pro-Delta(Z)Phe-Phe-NH(2) {[Delta(Z)Phe(3)]EM-2} (1), Tyr-Pro-Phe-Delta(Z)Phe-NH(2) {[Delta(Z)Phe(4)]EM-2} (2), and Tyr-Pro-Delta(Z)Phe-Delta(Z)Phe-NH(2) {[Delta(Z)Phe(3,4)]EM-2}(3) have been synthesized, their opioid receptor binding affinities and tissue bioassay activities were determined, and their conformational properties were examined. Compound 2 shows high mu opioid receptor selectivity and mu agonist activity comparable to those of the native peptide. The conformation adopted in solution and in the crystal by N-Boc-Tyr-Pro-Delta(Z)Phe-Phe-NH(2) (8) is reported.
Torino
Domenica
D
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A.Moro, 00185 Roma, Italy.
Mollica
Adriano
A
Pinnen
Francesco
F
Feliciani
Federica
F
Lucente
Gino
G
Fabrizi
Giancarlo
G
Portalone
Gustavo
G
Davis
Peg
P
Lai
Josephine
J
Ma
Shou-Wu
SW
Porreca
Frank
F
Hruby
Victor J
VJ
D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011957:Receptors, Opioid / Q000819:agonists; D013237:Stereoisomerism
D009842:Oligopeptides; D011957:Receptors, Opioid; C105294:endomorphin 2; D010649:Phenylalanine; C018632:phenyldehydroalanine