Xk. Nguyenle et al., PHARMACOLOGICAL CHARACTERIZATION OF SR-142801 - A NEW NONPEPTIDE ANTAGONIST OF THE NEUROKININ NK-3 RECEPTOR, Pharmacology, 52(5), 1996, pp. 283-291
Pharmacological and biochemical assays were performed to characterize
SR 142801, a new NK-3 receptor antagonist, and its [R]-enantiomer, SR
142806. The compounds were tested (1) in the guinea pig isolated ileum
stimulated with [MePhe(7)]NKB (NK-3 system) in order to evaluate onse
t and duration of action and to estimate the apparent affinity of the
antagonist in terms of pA(2) at 140 min after application; (2) in 6 se
lected monoreceptor systems, the rabbit (rb) vena cava for the NK-1rb
receptor, the rabbit pulmonary artery and the hamster (hs) urinary bla
dder for the NK-2rb and NK-2hs receptors, the rat (r) portal vein for
the NK-3r receptor, and in two multireceptor systems adequately treate
d with NK-1 or NK-2 receptor antagonists to obtain monoreceptor-mediat
ed biological responses (the rat urinary bladder treated with SR 48968
for evaluating the NK-1r and the guinea pig - gp - ileum treated with
CP-99994 for measuring the antagonist affinity on the NK-3gp receptor
), in order to evaluate the antagonist selectivity, and (3) in various
plasma membrane preparations containing NK-3-binding sites from rats,
guinea pigs, and man. The data presented indicate that SR 142801 is a
potent, fairly selective non-petide antagonist of the functional (pA(
2) 9.4) and binding (K-i 0.11 nmol/l) site of the guinea pig and human
(K-i 0.21 nmol/l) NK-3 receptors, while being much less active on the
NK-3 receptors of other species, particularly the rat (pA(2) 7.0; K-i
15 nmol/l). SR 142801 shows a slow onset of action and acts as a long
-lasting irreversible antagonist, specific for neurokinin receptors, e
specially the NK-3 sites of guinea pigs and man.