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-(1 H-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-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 (pA2 = 9.6) in the rabbit vena cava (NK1) bioassay and nanomolar affinity (pKi = 9.1) on the human NK1 receptor expressed by lymphoblastoma cells. It is devoid of mu-opiate affinity (Ki > 10(-4) M with respect to tritiated Tyr-DAla-Gly-MePhe-Gly-ol), has negligible calcium-channel affinity (estimated Ki = 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.
Bonnet
J
J
Institut de Recherches SERVIER, Suresnes, France.
Kucharczyk
N
N
Robineau
P
P
Lonchampt
M
M
Dacquet
C
C
Regoli
D
D
Fauchère
J L
JL
Canet
E
E
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004151:Dipeptides / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000097:blood / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D013777:Tetrazoles / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D004151:Dipeptides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C103198:S 18523; D013777:Tetrazoles; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P