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.

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 (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.

• Authors: 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, F Janssens
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 302 Issue 2 Pg. 696-709 (Aug 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12130734 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Allergens
• Butanols
• Malates
• Neurokinin-1 Receptor Antagonists
• Piperidines
• Platelet Activating Factor
• R116301
• Receptors, Neurokinin-1
• Substance P
• Histamine
• Capsaicin

Topics

• Administration, Oral
• Allergens
• Animals
• Butanols (pharmacology)
• Capsaicin (pharmacology)
• Cats
• Dogs
• Edema (chemically induced, 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