TY - JOUR T1 - 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 α<sub>1</sub>- and α<sub>2</sub>-Adrenergic Receptors: I. Receptorial, Neurochemical, and Electrophysiological Profile JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 38 LP - 53 VL - 292 IS - 1 AU - Mark J. Millan AU - Alain Gobert AU - Adrian Newman-Tancredi AU - Françoise Lejeune AU - Didier Cussac AU - Jean-Michel Rivet AU - Valérie Audinot AU - Agnès Adhumeau AU - Mauricette Brocco AU - Jean-Paul Nicolas AU - Jean A. Boutin AU - Nicole Despaux AU - Jean-Louis Peglion Y1 - 2000/01/01 UR - http://jpet.aspetjournals.org/content/292/1/38.abstract N2 - S18327 displayed modest affinity for human (h)D2 and hD3 receptors and high affinity for hD4receptors. At each, S18327 antagonized stimulation of [35S]guanosine-5′-O-(3-thio)triphosphate binding by dopamine (DA). It also blocked activation of mitogen-activated protein kinase at hD3 receptors. The affinity of S18327 at hD1 and hD5 sites was modest. S18327 showed pronounced affinity for human serotonin (h5-HT)2A receptors and human α1A-adrenergic receptors (hARs), at which it antagonized increases in intracellular Ca2+ concentration levels elicited by 5-HT and norepinephrine (NE), respectively. S18327 presented significant affinity for hα2A-ARs and antagonized NE-induced[35S]guanosine-5′-O-(3-thio)triphosphate binding both at these sites and at α2-ARs in rat amygdala. Reflecting blockade of α2-autoreceptors, S18327 enhanced firing of adrenergic neurons in locus ceruleus, accelerated hippocampal synthesis of NE, and increased dialysate levels of NE in hippocampus, accumbens, and frontal cortex. S18327 abolished inhibition of ventrotegmental area-localized dopaminergic neurons by apomorphine. However, S18327 alone did not affect their activity and only modestly enhanced cerebral turnover of DA and dialysate levels of DA in striatum and accumbens. In contrast, S18327 markedly increased dialysate levels of DA in frontal cortex, an action abolished by the selective α2-AR agonist, S18616. Finally, S18327 reduced synthesis and dialysate levels of 5-HT in striatum and suppressed firing of dorsal raphe-localized serotonergic neurons, an action attenuated by the α1-AR agonist cirazoline. In conclusion, S18327 possesses marked antagonist activity at α1-ARs and D4 and 5-HT2A receptors and less potent antagonist activity at α2-ARs and D1 and D2 receptors. Antagonism by S18327 of α2-ARs enhances adrenergic transmission and reinforces frontocortical dopaminergic transmission, whereas blockade of α1-ARs inhibits dorsal raphe-derived serotonergic pathways. As further described in the accompanying paper, this profile of activity may contribute to the potential antipsychotic properties of S18327. The American Society for Pharmacology and Experimental Therapeutics ER -