Pharmacological profile of (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an orally and centrally active neurokinin-1 receptor antagonist.
In comparison with a series of reference compounds, (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301) was characterized as a specific, orally, and centrally active neurokinin-1 (NK(1)) receptor antagonist with subnanomolar affinity for the human NK(1) receptor (K(i): 0.45 nM) and over 200-fold selectivity toward NK(2) and NK(3) receptors. R116301 inhibited substance P (SP)-induced peripheral effects (skin reactions and plasma extravasation in guinea pigs) and a central effect (thumping in gerbils) at low doses (0.08-0.16 mg/kg, s.c. or i.p.), reflecting its high potency as an NK(1) receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED(50) values: 3.2 mg/kg, s.c.; 0.72-2.5 mg/kg, p.o.). Even higher doses (11-25 mg/kg, s.c.) were required in mice (capsaicin-induced ear edema) and rats (SP-induced extravasation and salivation), consistent with lower affinity for the rodent NK(1) receptor and known species differences in NK(1) receptor interactions. R116301 inhibited the ocular discharge (0.034 mg/kg) but not the dyspnoea, lethality, or cough (>40 mg/kg, s.c.) induced by [betaALA(8)]-neurokinin A (NKA) (4-10) in guinea pigs, attesting to NK(1) over NK(2) selectivity. R116301 did not affect senktide-induced miosis (>5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK(3) receptor. R116301 was inactive in guinea pigs against skin reactions induced by histamine, platelet-aggregating factor, bradykinin, or Ascaris allergens (>10 mg/kg, s.c.). In all species, R116301 showed excellent oral over parenteral activity (ratio, 0.22-2.7) and a relatively long duration (6.5-16 h, p.o.). The data attest to the specificity and sensitivity of the animal models and support a role of NK(1) receptors in various diseases.
Megens
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Department of Discovery Research, Johnson & Johnson Pharmaceutical Research and Development, B-2340 Beerse, Belgium. amegens@janbe.jnj.com
Ashton
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Vermeire
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Vermote
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Hens
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KA
Hillen
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Fransen
J F
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Mahieu
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Heylen
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Leysen
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Jurzak
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MR
Janssens
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D000284:Administration, Oral; D000485:Allergens; D000818:Animals; D000440:Butanols / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D002415:Cats; D004285:Dogs; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005289:Ferrets; D005849:Gerbillinae; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007700:Kinetics; D008293:Malates; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor / Q000494:pharmacology; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000008:administration & dosage*; D012472:Salivation / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology; D013997:Time Factors
D000485:Allergens; D000440:Butanols; D008293:Malates; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor; C400708:R116301; D018040:Receptors, Neurokinin-1; D013373:Substance P; D006632:Histamine; D002211:Capsaicin