TY - JOUR T1 - MEN 11270, A Novel Selective Constrained Peptide Antagonist with High Affinity at the Human B<sub>2</sub> Kinin Receptor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1250 LP - 1256 VL - 289 IS - 3 AU - Stefania Meini AU - Laura Quartara AU - Anna Rizzi AU - Riccardo Patacchini AU - Paola Cucchi AU - Alessandro Giolitti AU - Girolamo Calò AU - Domenico Regoli AU - Marco Criscuoli AU - Carlo A. Maggi Y1 - 1999/06/01 UR - http://jpet.aspetjournals.org/content/289/3/1250.abstract N2 - We investigated the pharmacological profile of MEN 11270, or H-D-Arg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7γ-10 α), 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, inhibiting3H-bradykinin (BK) with a pKivalue 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) ≈ MEN 11270 (pKi = 10.3) ≈ B9430 (pKi = 10.0) &gt; B9858 (pKi = 8.0) &gt; FR173657 (pKi = 7.6) &gt; WIN64338 (pKi = 7.2) &gt; Lys-[des-Arg9,Leu8]-BK (pKi &lt; 6) &gt; [des-Arg9,Leu8]-BK (pKi &lt; 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 &lt; 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 μM) 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 β-turn conformation preserves a high affinity for the interaction of Icatibant with the B2 kinin receptor. The American Society for Pharmacology and Experimental Therapeutics ER -