Vol. 302, Issue 2, 696-709, August 2002

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

A. A. H. P. Megens, D. Ashton, J. C. A. Vermeire, P. C. M. Vermote, K. A. Hens, L. C. Hillen, J. F. Fransen, M. Mahieu, L. Heylen, J. E. Leysen, M. R. Jurzak and F. Janssens

Department of Discovery Research Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

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 (NK₁) receptor antagonist with subnanomolar affinity for the human NK₁ receptor (K_i: 0.45 nM) and over 200-fold selectivity toward NK₂ and NK₃ 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 NK₁ receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED₅₀ 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 NK₁ receptor and known species differences in NK₁ 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 [ALA⁸]-neurokinin A (NKA) (4-10) in guinea pigs, attesting to NK₁ over NK₂ selectivity. R116301 did not affect senktide-induced miosis (>5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK₃ 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 NK₁ receptors in various diseases.