Pharmacology of CP-99,994; a nonpeptide antagonist of the tachykinin neurokinin-1 receptor.
J Pharmacol Exp Ther
; 267(1): 472-9, 1993 Oct.
Article
em En
| MEDLINE
| ID: mdl-7693914
ABSTRACT
(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds selectively and with high affinity (Ki = 0.25 nM) to neurokinin (NK)-1 tachykinin receptors in a human cell line and in guinea pigs where it acts as an antagonist as evidenced by its blockade of substance P-induced excitation of locus coeruleus neurons in vitro. Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potently blocked (ID50 = 4 mg/kg) the leakage of Evans blue dye into trachea and bronchi elicited by exposure of guinea pigs to aerosol capsaicin (1 mM). CP-99,994 has reduced affinity (IC50 = 3 microM) for the L-type calcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonpeptide antagonist. Thus, CP-99,994 represents an important pharmacological tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseases.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Receptores da Neurocinina-1
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
1993
Tipo de documento:
Article