WAY-100635 was initially developed in the mid-1990s and was recognized as the first highly potent and selective “silent” antagonist of the serotonin 5-HT1A receptor.
Early pharmacological evaluations of WAY-100635 demonstrated that it was a selective antagonist of 5-HT1A receptors. And WAY-100635 displays at least 100-fold selectivity for 5-HT1A receptors over more than 40 other receptors, channels, and transporters. Unlike earlier 5- HT1A receptor antagonists, WAY-100635 behaves as a pure antagonist in models of both presynaptic and postsynaptic 5-HT1A receptor activation.
Especially, this finding was followed by the development of a superior radioligand, [ 11C]carbonyl-WAY-100635, which lacks brain-penetrating metabolites. This compound still as the best radioligand available for PET imaging to investigate the in vivo pharmacology, physiological function, expression level, and anatomical distribution of 5-HT1A receptors.
In connection with the ongoing studies in our laboratory, we observed a surprising pharmacological action of WAY-100635 that suggested that it might have potent activity at dopamine D2-like receptors. This screening revealed that both WAY-100635 and its major metabolite, WAY-100634, had high affinity for the dopamine D4.2 receptor. Subsequent experiments examined the functional activity and binding affinities of WAY-100635 and WAY-100634 in HEK 293 cells stably expressing dopamine D2L or D4.4 receptors.
WAY-100635 and its major metabolite, WAY-100634, were potent agonists with high affinity at dopamine D4 receptors. This result raises the possibility that the neuroanatomical, physiological, and cellular data generated using WAY-100635 or WAY-100634 may reflect a dopamine D4 receptor component.
Moreover, WAY-100635 displays 940, 370, and 16 nM binding affinities at D2L, D3, and D4.2 receptors, respectively. Saturation analyses demonstrat that the Kd of [3H] WAY-100635 at D4.2 receptors is 2.4 nM. And it is a potent agonist in HEK-D4.4 cells with EC50 of 9.7 nM. Also WAY-100635 possesses high affinity for D4.4 receptor (3.3 nM).
What’s more, WAY-100635 (1 mg/kg; subcutaneous injection; male Sprague-Dawley rats) treatment abolishes the reduction of the severity of abstinence signs induced by Rhodiola rosea administration in nicotine-dependent rat.