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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 302; no. 2; pp. 696 - 709
• Main Authors: Megens, A A H P, Ashton, D, Vermeire, J C A, Vermote, P C M, Hens, K A, Hillen, L C, Fransen, J F, Mahieu, M, Heylen, L, Leysen, J E, Jurzak, M R, Janssens, F
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.2002
• Subjects: Administration, Oral; Allergens; Animals; Butanols - pharmacology; Capsaicin - pharmacology; Cats; Dogs; Edema - chemically induced; Edema - physiopathology; Ferrets; Gerbillinae; Guinea Pigs; Histamine - pharmacology; Kinetics; Malates; Mice; Motor Activity - drug effects; Neurokinin-1 Receptor Antagonists; Piperidines; Platelet Activating Factor - pharmacology; Rabbits; Receptors, Neurokinin-1 - administration & dosage; Salivation - drug effects; Substance P - pharmacology; Time Factors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.034348

In comparison with a series of reference compounds, (2 R - 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 [βALA 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.