A serotonin 5-HT1A antagonist
5-HT1A receptors mediate various serotonergic functions and may be implicated in various pathologies including depressive and anxiety disorders, Alzheimer’s disease, and schizophrenia. WAY-100635 is a potential SPECT ligands for the 5-HT1A receptor.
In vitro: WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT, to rat hippocampal membranes with a plC50 of 8.87. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HTIA receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA 2 value (at 0.3 nM) of 9.71 [2].
In vivo: WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. [2].
Clinical trial: Using the ligand [11C]-WAY100635, an open label, non-randomized positron emission tomography study in healthy male subjects has been conducted to investigate brain 5-HT1A receptor occupancy, pharmacokinetics and safety of single oral doses of GSK163090.
参考文献:
[1] Al Hussainy R, Verbeek J, van der Born D, Braker AH, Leysen JE, Knol RJ, Booij J, Herscheid JK.?
Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A receptor.? J Med Chem. 2011;54(10):3480-91.
[2] Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, Fletcher A.? A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol. 1995;281(1):81-8.
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