NK-3 receptors are G-protein coupled receptors activated by mammalian tachykinins, which can modulate dopaminergic neurotransmission, and thus may play a role in development and expression of behavioral sensitization[3]. SB-222200 is a human NK-3 receptor (hNK-3R) antagonist. SB-222200 inhibited 125I-[MePhe7] neurokinin B (NKB) binding to Chinese hamster ovary (CHO) cell membranes stably expressing the hNK-3 receptor with a Ki of 4.4 nM and antagonized NKB-induced Ca2+ mobilization in HEK 293 cells stably expressing the hNK-3 receptor with an IC50 of 18.4 nM. SB-222200 was selective for hNK-3 receptors compared with hNK-1 (Ki > 100,000 nM) and hNK-2 receptors (Ki = 250 nM). In HEK 293 cells transiently expressing murine NK-3 receptors, SB-222200 inhibited binding of 125I-[MePhe7]NKB (Ki = 174 nM) and antagonized NKB (1 nM)-induced calcium mobilization (IC50 = 265 nM). In mice oral administration of SB-222200 produced dose-dependent inhibition of behavioral responses induced by i.p. or intracerebral ventricular administration of the NK-3 receptor-selective agonist, senktide, with ED50 value of approximately 5 mg/kg. Pharmacokinetic evaluation of SB-222200 in rat after oral administration (8 mg/kg) indicated sustained plasma concentrations (Cmax) = 400 ng/mL) and bioavailability of 46% [2]. Administration of SB-222200 (5 mg/kg, s.c.) prior to repeated cocaine (20 mg/kg, i.p.) prevented the development of sensitized responses after a cocaine challenge.
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