TY - JOUR T1 - Pharmacological Profile of (2<em>R</em>-<em>trans</em>)-4-[1-[3,5-bis(Trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-<em>N</em>-(2,6-dimethylphenyl)-1-acetamide (<em>S</em>)-Hydroxybutanedioate (R116301), an Orally and Centrally Active Neurokinin-1 Receptor Antagonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 696 LP - 709 DO - 10.1124/jpet.102.034348 VL - 302 IS - 2 AU - A. A. H. P. Megens AU - D. Ashton AU - J. C. A. Vermeire AU - P. C. M. Vermote AU - K. A. Hens AU - L. C. Hillen AU - J. F. Fransen AU - M. Mahieu AU - L. Heylen AU - J. E. Leysen AU - M. R. Jurzak AU - F. Janssens Y1 - 2002/08/01 UR - http://jpet.aspetjournals.org/content/302/2/696.abstract N2 - 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 (Ki: 0.45 nM) and over 200-fold selectivity toward NK2 and NK3receptors. 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 NK1receptor 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 (&gt;40 mg/kg, s.c.) induced by [βALA8]-neurokinin A (NKA) (4–10) in guinea pigs, attesting to NK1 over NK2 selectivity. R116301 did not affect senktide-induced miosis (&gt;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 (&gt;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. The American Society for Pharmacology and Experimental Therapeutics ER -