A water-soluble, stable dipeptide NK1 receptor-selective neurokinin receptor antagonist with potent in vivo pharmacological effects: S18523

The potassium salt of a chemically stabilized dipeptide, {1-[4-(1H-tetrazol-5-yl)butyI]indol-3-yl}carbony-Hyp-Nal-N(methyl)-Bzl, (Hyp = (R)-4-hydroxy-L-proline; Nal = 3-L-(beta-naphthyl)-alanine), S18523, is described as a new water-soluble, potent and selective NK1 receptor antagonist. The low molecular weight antagonist (M(r) = 736) displays nanomolar potency (pA(2) = 9.6) in the rabbit vena cava (NK1) bioassay and nanomolar affinity (pK(i) = 9.1) on the human NK1 receptor expressed by lymphoblastoma cells. It is devoid of mu-opiate affinity (K-i > 10(-4) M with respect to tritiated Tyr-DAla-Gly-MePhe-Gly-ol), has negligible calcium-channel affinity (estimated K-i = 2.6 x 10(-5) M, with respect to isradipine) and does not cause peritoneal mast-cell degranulation. S18523 has strong antinociceptive effects in three classical pain tests in vivo both by i.v. and p.o. routes. The dipeptide potently antagonizes bronchoconstriction provoked by exogenous substance P in the guinea-pig and acts longer than the non-peptide antagonist CP99994, when administered as aerosol. Finally, S18523 displays antiinflammatory properties, since it dose-dependently inhibits substance P-induced plasma extravasation both in the bladder (ID50 = 0.18 mg/kg i.v.) and bronchi (ID50 = 0.14 mg/kg i.v.) of the guinea-pig.