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.

No abstract

Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. ]-GTPgS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gai than Gao activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.

No abstract

No abstract

The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D 2SHORT(S) , hD 2LONG(L) , hD 3 , and hD 4.4 receptors and at h␣ 2A -, h␣ 2B -, h␣ 2C -, and h␣ 1A -adrenoceptors (ARs). As determined by guanosine 5Ј-O-(3-[ S]GTP␥S) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D 2 -like" sites. However, at hD 2S receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E maxՆ 100%); TL99, talipexole, and apomorphine were highly efficacious (79 -92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40 -55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD 2L receptors, with terguride and roxindole acting as antagonists. At hD 3 receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD 4 receptors, highest efficacies (ϳ70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD 2S versus hD 2L sites were highly correlated (r ϭ 0.79), they correlated only modestly to hD 3 /hD 4 sites (r ϭ 0.44 -0.59). In [ 35 S]GTP␥S studies of h␣ 2A -ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at h␣ 2B -and h␣ 2C -ARs. Using (Wang et al., 2000). As shown in the accompanying article , therapeutically used antiparkinson agents recognize D 2S and D 2L isoforms with similar affinity, and many antiparkinson agents also interact with dopamine D 3 receptors. Although the density of striatal D 3 receptors is reduced upon degeneration of nigrostriatal dopaminergic pathways, exposure to L-DOPA may induce their up-regulation, reflecting complex regulatory mechanisms involving dopamine D 1 receptors and brainderived neurotrophic factor (Quik et al., 2000;Guillin et al., 2001;Joyce, 2001). Nevertheless, the precise nature of functional interrelationships among D 3 , D 2 , and D 1 receptors, and the implication of D 3 receptors in the therapeutic comArticle, publication date, and citation information can be found at