Nemonapride

Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT_1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT_1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes.

The [³⁵S]GTPγS binding assay for G_i/o proteins coupled with 5-HT_1A receptors was performed in rat brain membranes and postmortem human brain membranes.

The specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT_1A receptor agonism, involvement of other components, e.g., 5-HT_1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT_1A receptor neutral antagonist. Negligible stimulatory effects were obtained as to lurasidone and asenapine.

Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT_1A receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group.

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D₃ versus D₂ agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD₃ and hD_2L receptors, (+)PHNO revealed high affinity at hD_4.4 but not hD₁ or hD₅ receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT_1A and h5-HT₇. (+)PHNO behaved as a full agonist at hD_4.4 and h5-HT_1A receptors with potencies comparable to its actions at hD₃ and hD_2L receptors, and with less potency at 5-HT₇ receptors. In binding assays with membranes derived from cells co-expressing hD₃ and hD_2L receptors and labeled with [³H]Nemonapride or [³H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD₃or hD_2L receptors, suggesting that (+)PHNO promotes formation of hD₃-hD_2L heterodimers. Further, in cells co-expressing hD₃ and hD_2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD_2L receptors. In conclusion, (+)PHNO is a potent agonist at hD₄.₄, h5-HT_1A and h5-HT₇ as well as hD₃ and hD_2L receptors, and it potently activates dopamine hD₃-hD_2L heterodimers. These interactions should be considered when interpreting PET studies with [¹¹C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.