title: MEN 11270, A novel selective constrained peptide antagonist with high affinity at the human B2 kinin receptor.
abstract: We investigated the pharmacological profile of MEN 11270, or H-D-Arg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-10 alpha), a conformationally constrained derivative of the B2 kinin receptor antagonist Icatibant. MEN 11270 bound with high-affinity to the B2 kinin receptor constitutively expressed by WI38 human fibroblasts, inhibiting 3H-bradykinin (BK) with a pKi value of 10.3 +/- 0.08 (n = 5). The rank order of affinity of several peptide and nonpeptide antagonists was also assessed: Icatibant (pKi = 10.6) approximately MEN 11270 (pKi = 10.3) approximately B9430 (pKi = 10.0) > B9858 (pKi = 8.0) > FR173657 (pKi = 7.6) > WIN64338 (pKi = 7.2) > Lys-[des-Arg9, Leu8]-BK (pKi < 6) > [des-Arg9,Leu8]-BK (pKi < 5). MEN 11270 showed a low affinity in inhibiting 3H-Lys-[des-Arg9]-BK binding at the human B1 kinin receptor constitutively expressed by the same cells (pKi 6.0 +/- 0.33; n = 3). MEN 11270 showed no binding affinity (pIC50 < 5.5) at 29 different receptors and ion channels. In the human umbilical vein contraction assay, MEN 11270, shifted the concentration-response curve to BK to the right in a concentration-dependent manner (pA2 8.14 +/- 0.22, n = 7). The Schild plot was linear (slope 0.95 +/- 0.11), consistent with a competitive antagonism. In the same bioassay, MEN 11270 (10 microM) did not affect the concentration-response curve to the B1 agonist Lys-[des-Arg9]-BK nor the contractile responses elicited by noradrenaline or serotonin. These findings indicate MEN 11270 as an antagonist at the human B2 kinin receptor, with potency and selectivity comparable to those of the linear peptide antagonist, supporting the hypothesis that a constrained C-terminal beta-turn conformation preserves a high affinity for the interaction of Icatibant with the B2 kinin receptor.
authors.affiliation: Department of Pharmacology, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Meini
authors.forename: L
authors.initials: L
authors.lastname: Quartara
authors.forename: A
authors.initials: A
authors.lastname: Rizzi
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: P
authors.initials: P
authors.lastname: Cucchi
authors.forename: A
authors.initials: A
authors.lastname: Giolitti
authors.forename: G
authors.initials: G
authors.lastname: Calò
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.forename: M
authors.initials: M
authors.lastname: Criscuoli
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001667:Binding, Competitive; D001681:Biological Assay; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D011247:Pregnancy; D011804:Quinolines / Q000494:pharmacology; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014471:Umbilical Veins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; C105311:FR 173657; C119318:MEN 11270; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D012701:Serotonin; C065679:icatibant; D001920:Bradykinin; D009638:Norepinephrine