IDENTIFICATION OF BINDING-SITES FOR SR-46349B, A 5-HYDROXYTRYPTAMINE(2) RECEPTOR ANTAGONIST, IN RODENT BRAIN

SR 46349B belongs to a new class of compounds (propenone oxime ether derivative) that inhibit 5-hydroxytryptamine (HT), receptors in vitro and in vivo. (H-3) SR 46349B has been shown to bind with high affinity (K(d) = 1.20 nM) to a single class of sites in rat prefrontal cortical membranes. The maximum binding capacity (B(max) = 0.262 pmol/mg of protein) is similar to that found for other classes of 5-HT, receptor antagonists. Although the highest density of specific (H-3) SR 46349B binding was found in cortex tissue, specific binding was also detectable in other brain areas. Among various receptor or channel ligands [including alpha or beta adrenergic, dopamine (D1 or D2), histamine (H-1 or H-2), 5-HT subclasses (5-HT1, 5-HT3), muscarinic and Na+ and Ca2+ channel blockers] only 5-HT, receptor effectors were able to displace (H-3) SR 46349B. In addition, the type of inhibition exerted by known 5-HT, receptor antagonists such as ketanserin and ritanserin was investigated by saturation studies. In vivo, (H-3) SR 46349B bound predominantly in mouse brain regions containing 5-HT, receptors. This binding was displaced by SR 46349B, ketanserin and ritanserin following oral administration. From these results we suggest that SR 46349B in its tritiated form is a useful tool to label the 5-HT2 receptor in vitro and in vivo.