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.
Footnotes
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↵1 No confidence limits. The ED50 was estimated based on blockade of retching in three of five animals at the highest tested dose of 10 mg/kg.
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DOI: 10.1124/jpet.102.034348
- Abbreviations:
- SP
- substance P
- NK
- neurokinin
- NKA
- neurokinin A
- R116301
- (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate
- CGP49823
- (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-4-ylmethylamino)piperidine
- CP-96345
- (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine
- CP-99994
- (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
- GR-203040
- (2S,3S)-(2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine
- MK-869 or L-754030
- aprepitant
- L-760,735
- 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-trioazol-4-yl)methyl-3-(5)-phenyl)morpholine
- RP-67580
- (3aR,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]perhydroisoindol-4-one
- SDZ-NKT-343
- 2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide
- SR-140333
- nolpitantium
- SR-48968
- saredutant
- SR-142801
- osanetant
- Y-24180
- (±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
- LY255582
- (3R,4R)-3,4-dimethyl-1-[(3S)-3-hydroxy-3-cyclohexyl-propyl]-4-(3-hydroxyphenyl)piperidine
- PAF
- platelet-aggregating factor
- 5-HT
- serotonin
- MDL-103392
- 4-piperidinecarboxamide, 1-[2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-3-pryrrolidinyl]ethyl]-4-phenyl
- MDL-105212
- (3R)-MDL-103392
- Received February 6, 2002.
- Accepted April 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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