Pharmacological Profile of (2 R-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

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Abstract
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 (>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 (>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.

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