LF 16.0335

In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1‐[[3‐[(2,4‐dimethylquinolin‐8‐yl)oxymethyl]‐2,4‐dichloro‐phenyl]sulphonyl] ‐2(S) ‐ [[4 ‐[4‐(aminoiminomethyl)phenylcarbonyl]piperazin‐1‐yl]carbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor.LF 16.0335 displaced [3H]‐BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84±0.39 nM, 1.26±0.68 nM and 2.34±0.36 nM, respectively.In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, Bmax values of [3H]‐BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist.LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1 μM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1 μM was obtained.BK stimulates in a concentration‐dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration‐response‐curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 μM) without reduction of the maximum. LF 16.0335 inhibited the concentration‐contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30±0.30 with a Schild plot slope that was not different from unity.These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor.British Journal of Pharmacology (1998) 125, 365–372; doi:10.1038/sj.bjp.0702083