title: A rational approach to the design and synthesis of a new bradykinin B(1) receptor antagonist.
abstract: We have previously synthesized a potent and selective B(1) bradykinin receptor antagonist, JMV1645 (H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH), containing a dipeptide mimetic ((3S)-amino-5-carbonylmethyl-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety) at the C-terminal. Analogues of this potent B(1) bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro¿4. 5decan-4-one ring system were synthesized. Among these analogues, compound JMV1640 (1) was found to have an affinity of 24.10 +/- 9.48 nM for the human cloned B(1) receptor. It antagonized the ¿des-Arg(10)-kallidin-induced contraction of the human umbilical vein (pA(2) = 6.1 +/- 0.1). Compound 1 was devoid of agonist activity at the kinin B(1) receptor. Moreover, it did not bind to the human cloned B(2) receptor. Therefore, JMV1640 constitutes a lead compound for the rational search of nonpeptide B(1) receptor analogues based on the BK sequence.
authors.affiliation: Laboratoire des Aminoacides Peptides et Protéines, UMR5810-CNRS, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier Cédex, France.
authors.forename: P
authors.initials: P
authors.lastname: Bedos
authors.forename: M
authors.initials: M
authors.lastname: Amblard
authors.forename: G
authors.initials: G
authors.lastname: Subra
authors.forename: P
authors.initials: P
authors.lastname: Dodey
authors.forename: J M
authors.initials: JM
authors.lastname: Luccarini
authors.forename: J L
authors.initials: JL
authors.lastname: Paquet
authors.forename: D
authors.initials: D
authors.lastname: Pruneau
authors.forename: A
authors.initials: A
authors.lastname: Aumelas
authors.forename: J
authors.initials: J
authors.lastname: Martinez
mesh_terms: D000818:Animals; D065168:Bradykinin Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D043783:Receptor, Bradykinin B1; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology
chemical_list: D065168:Bradykinin Receptor Antagonists; C410937:JMV 1640; D009842:Oligopeptides; D043783:Receptor, Bradykinin B1; D013841:Thiazepines