Vol. 292, Issue 1, 38-53, January 2000

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 ₁- and ₂-Adrenergic Receptors: I. Receptorial, Neurochemical, and Electrophysiological Profile

Mark J. Millan, Alain Gobert, Adrian Newman-Tancredi, Françoise Lejeune, Didier Cussac, Jean-Michel Rivet, Valérie Audinot, Agnès Adhumeau, Mauricette Brocco, Jean-Paul Nicolas, Jean A. Boutin, Nicole Despaux and Jean-Louis Peglion

Psychopharmacology (M.J.M., A.G., A.N.-T., F.L., D.C., J.-M.R., V.A., A.A., M.B.) and Molecular and Cellular Pharmacology (J.-P.N., J.A.B.) Departments, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, Paris, France; and Chemistry B Department, Institut de Recherches Servier, Centre de Recherches de Suresnes, Suresnes, France (N.D., J.-L.P.)

S18327 displayed modest affinity for human (h)D₂ and hD₃ receptors and high affinity for hD₄ receptors. 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 _1A-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 h_2A-ARs and antagonized NE-induced[³⁵S]guanosine-5'-O-(3-thio)triphosphate binding both at these sites and at ₂-ARs in rat amygdala. Reflecting blockade of ₂-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 ₂-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 ₁-AR agonist cirazoline. In conclusion, S18327 possesses marked antagonist activity at ₁-ARs and D₄ and 5-HT_2A receptors and less potent antagonist activity at ₂-ARs and D₁ and D₂ receptors. Antagonism by S18327 of ₂-ARs enhances adrenergic transmission and reinforces frontocortical dopaminergic transmission, whereas blockade of ₁-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.