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.

The principal soy phytoestrogen genistein has an array of biological actions. It binds to estrogen receptor (ER) ␣ and ␤ and has ER-mediated estrogenic effects. In addition, it has antiestrogenic effects as well as non-ERmediated effects such as inhibition of tyrosine kinase. Because of its complex biological actions, the molecular mechanisms of action of genistein are poorly understood. Here we show that genistein dose-dependently increases estrogenic transcriptional activity in mesenchymal progenitor cells, but its biological effects on osteogenesis and adipogenesis are different. At low concentrations (<1 M), genistein acts as estrogen, stimulating osteogenesis and inhibiting adipogenesis. At high concentrations (>1 M), however, genistein acts as a ligand of PPAR␥, leading to up-regulation of adipogenesis and down-regulation of osteogenesis.Transfection experiments show that activation of PPAR␥ by genistein at the micromolar concentrations down-regulates its estrogenic transcriptional activity, while activation of ER␣ or ER␤ by genistein downregulates PPAR␥ transcriptional activity. Genistein concurrently activates two different transcriptional factors, ERs and PPAR␥, which have opposite effects on osteogenesis or adipogenesis. As a result, the balance between activated ERs and PPAR␥ determines the biological effects of genistein on osteogenesis and adipogenesis. Our findings may explain distinct effects of genistein in different tissues.

Melatonin has a key role in the circadian rhythm relay to periphery organs. Melatonin exerts its multiple roles mainly through two seven transmembrane domain, G-coupled receptors, namely MT1 or MT2 receptors. A pharmacological characterization of these human cloned melatonin hMT1 and hMT2 receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[125I]-iodo-melatonin binding assay and a [35S]-GTPgammaS functional assay. Both reference compounds and new chemically diverse ligands were evaluated. Binding affinities at each receptor were found to be comparable on either HEK-293 or CHO cell membranes. Novel non-selective or selective hMT1 and hMT2 ligands are described. The [35S]-GTPgammaS functional assay was used to define the functional activity of these compounds which included partial, full agonist and/or antagonist activity. None of the compounds acted as an inverse agonist. We report new types of selective antagonists, such as S 25567 and S 26131 for MT1 and S 24601 for MT2. These studies brought other new molecular tools such as the selective MT1 agonist, S 24268, as well as the non-selective antagonist, S 22153. Finally, we also discovered S 25150, the most potent melatonin receptor agonist, so far reported in the literature.

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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

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In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.