S18327 (1-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1) and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile

S18327 displayed modest affinity for human (h) D-2 and hD(3) receptors and high affinity for hD(4) receptors. At each, S18327 antagonized stimulation of [S-35] guanosine-5'-O-(3-thio) triphosphate binding by dopamine (DA). It also blocked activation of mitogen-activated protein kinase at hD(3) recep tors. The affinity of S18327 at hD(1) and hD(5) sites was modest. S18327 sh owed pronounced affinity for human serotonin (h5-HT)(2A) receptors and huma n alpha(1A)-adrenergic receptors (hARs), at which it antagonized increases in intracellular Ca2+ concentration levels elicited by 5-HT and norepinephr ine (NE), respectively. S18327 presented significant affinity for h alpha(2 A)-ARs and antagonized NE-induced[S-35] guanosine-5'-O-(3-thio) triphosphat e binding both at these sites and at alpha(2)-ARs in rat amygdala. Reflecti ng blockade of alpha(2)-autoreceptors, S18327 enhanced firing of adrenergic neurons in locus ceruleus, accelerated hippocampal synthesis of NE, and in creased dialysate levels of NE in hippocampus, accumbens, and frontal corte x. S18327 abolished inhibition of ventrotegmental area-localized dopaminerg ic neurons by apomorphine. However, S18327 alone did not affect their activ ity and only modestly enhanced cerebral turnover of DA and dialysate levels of DA in striatum and accumbens. In contrast, S18327 markedly increased di alysate levels of DA in frontal cortex, an action abolished by the selectiv e alpha(2)-AR agonist, S18616. Finally, S18327 reduced synthesis and dialys ate levels of 5-HT in striatum and suppressed firing of dorsal raphe-locali zed serotonergic neurons, an action attenuated by the alpha(1)-AR agonist c irazoline. In conclusion, S18327 possesses marked antagonist activity at al pha(1)-ARs and D-4 and 5-HT2A receptors and less potent antagonist activity at alpha(2)-ARs and D-1 and D-2 receptors. Antagonism by S18327 of alpha(2 )-ARs enhances adrenergic transmission and reinforces frontocortical dopami nergic transmission, whereas blockade of alpha(1)-ARs inhibits dorsal raphe -derived serotonergic pathways. As further described in the accompanying pa per, this profile of activity may contribute to the potential antipsychotic properties of S18327.