Because little comparative information is available concerning receptor profiles of antiparkinson drugs, affinities of 14 agents were determined at diverse receptors implicated in the etiology and/or treatment of Parkinson's disease: human (h)D 1 , hD 2S , hD 2L , hD 3 , hD 4 , and hD 5 receptors; human 5-hydroxytryptamine (5-HT) 1A , h5-HT 1B , h5-HT 1D , h5-HT 2A , h5-HT 2B , and h5-HT 2C receptors; h␣ 1A -, h␣ 1B -, h␣ 1D -, h␣ 2A -, h␣ 2B -, h␣ 2C -, rat ␣ 2D -, h␤ 1 -, and h␤ 2 -adrenoceptors (ARs); and native histamine 1 receptors. A correlation matrix (294 pK i values) demonstrated substantial "covariance". Correspondingly, principal components analysis revealed that axis 1, which accounted for 76% variance, was associated with the majority of receptor types: drugs displaying overall high versus modest affinities migrated at opposite extremities. Axis 2 (7% of variance) differentiated drugs with high affinity for hD 4 and H 1 receptors versus h␣ 1 -AR subtypes. Five percent of variance was attributable to axis 3, which distinguished drugs with marked affinity for h␤ 1 -and h␤ 2 -ARs versus hD 5 and 5-HT 2A receptors. Hierarchical (cluster) analysis of global homology generated a dendrogram differentiating two major groups possessing low versus high affinity, respectively, for multiple serotonergic and hD 5 receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD 2 , hD 3 , and hD 4 receptors, whereas piribedil and talipexole recognized dopaminergic receptors and h␣ 2 -ARs. Within the second group, lisuride and terguride manifested high affinities for all sites, with roxindole/bromocriptine, cabergoline/pergolide, and 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin (TL99)/apomorphine comprising three additional subclusters of closely related ligands. In conclusion, an innovative multivariate analysis revealed marked heterogeneity in binding profiles of antiparkinson agents. Actions at sites other than hD 2 receptors likely participate in their (contrasting) functional profiles.

Agomelatine (S20098) displayed pK i values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT) 2C receptors, respectively. It also interacted with h5-HT 2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT 2A (Ͻ5.0/5.3) and 5-HT 1A (Ͻ5.0/5.2) receptors, and negligible (Ͻ5.0) affinity for other 5-HT receptors. In antibody capture/ scintillation proximity assays, agomelatine concentration dependently and competitively abolished h5-HT 2C receptor-mediated activation of Gq/11 and Gi 3 (pA 2 values of 6.0 and 6.1). As measured by [ 3 H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT 2C (pK B value of 6.1) and h5-HT 2B (pK B value of 6.6) receptors. In vivo, it dose dependently blocked induction of penile erections by the 5-HT 2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[a]inden-3-yl) ethylamine (Ro60,0332). Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected by agomelatine, it abolished their inhibition by Ro60,0175. Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N- [2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely reflect blockade of 5-HT 2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, in distinction to agomelatine, melatonin showed negligible activity at 5-HT 2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT 2B and 5-HT 2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.

The present study evaluated, via a combined electrophysiological and dialysis approach, the potential influence of serotonin (5-HT)(2C) as compared to 5-HT(2A) and 5-HT(2B) receptors on dopaminergic, adrenergic, and serotonergic transmission in frontal cortex (FCX). Whereas the selective 5-HT(2A) antagonist MDL100,907 failed to modify extracellular levels of dopamine (DA), noradrenaline (NA) or 5-HT simultaneously quantified in single dialysate samples of freely-moving rats, the 5-HT(2B)/5-HT(2C) antagonist SB206,553 dose-dependently increased levels of DA and NA without affecting those of 5-HT. This action was attributable to 5-HT(2C) receptor blockade inasmuch as the selective 5-HT(2C) antagonist SB242,084 likewise increased FCX levels of DA and NA, whereas the selective 5-HT(2B) antagonist SB204,741 was ineffective. Further, the preferential 5-HT(2C) receptor agonist Ro60-0175 dose-dependently depressed FCX levels of DA. The suppressive influence of 5-HT(2C) receptors on DA release was also expressed on mesolimbic and nigrostriatal dopaminergic pathways, in that levels of DA in nucleus accumbens and striatum were likewise reduced by Ro60-0175 and elevated, though less markedly, by SB206,553. In line with the above findings, Ro60-0175 dose-dependently decreased the firing rate of ventrotegmental dopaminergic and locus coeruleus (LC) adrenergic perikarya, whereas their activity was dose-dependently enhanced by SB206,553. Furthermore, SB206,553 transformed the firing pattern of ventrotegmental dopaminergic neurons into a burst mode. In contrast to SB206,553, MDL100,907 had little affect on the firing rate of dopaminergic or adrenergic neurons. In conclusion, as compared to 5-HT(2A) and 5-HT(2B) receptors, 5-HT(2C) receptors exert a tonic, suppressive influence on the activity of mesocortical - as well as mesolimbic and nigrostriatal - dopaminergic pathways, likely via indirect actions expressed at the level of their cell bodies. Frontocortical adrenergic, but not serotonergic, transmission is also tonically suppressed by 5-HT(2C) receptors.

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