(GABAergic) 2 dynorphinergic neuron, which also expresses substance P (SP), and the GABAergic enkephalinergic neuron (4, 5). In fact, results obtained with in vivo techniques indicate that dopamine exerts differential effects on the two types of GABAergic efferent neurons, by acting on stimulatory D 1 receptors localized in the GABAergic SP-dynorphinergic neurons and inhibitory D 2 receptors localized in the GABAergic enkephalinergic neurons (6 -8). However, functional D 1 -like and D 2 -like receptors, as well as significant levels of D 1 and D 2 receptor mRNA expression, were detected in acutely dissociated striatonigral neurons (9). A more detailed and extensive analysis of the mRNA expression of the different receptor subtypes indicated that there is a limited subset of striatal neurons (ϳ15% of all GABAergic efferent neurons) with a mixed phenotype of GABAergic SP-dynorphinergic and GABAergic enkephalinergic neurons, with D 1 and D 2 receptors (10). This co-expression of D 1 and D 2 receptors has been confirmed in neostriatal neurons at the confocal microscopy level (11,12). George and coworkers (12, 13) have also found evidence for D 1 -D 2 receptor heteromerization (by co-immunoprecipitation) and for the generation of a unique pharmacology of the D 1 -D 2 receptor heteromer, with binding to selective ligands

We have recently reported that two typical G s -coupled receptors, the ␤ 2 -adrenergic receptor and the receptor for prostaglandin E 1 , stimulate phospholipase C-⑀ (PLC- Activation of mitogen-activated protein (MAP) 1 kinases plays a prominent role in many cellular responses to a large variety of membrane receptors. Initially identified as signal transducers of growth factor receptors with intrinsic tyrosine kinase activity, activation of MAP kinases, specifically of the extracellular signal-regulated kinases 1 and 2 (ERK1/2), is now also recognized as a major signal transduction pathway of many receptors coupled to heterotrimeric G proteins. ERK activation by these second messenger-generating receptors is apparently accomplished by diverse molecular mechanisms, depending on the cell types studied as well as the receptor and the heterotrimeric G protein involved (1-5).⑀The cAMP-producing G s -coupled receptors play a rather unique role in ERK activation. These receptors inhibit ERK activation by growth factor receptors in several cell types while stimulating this cellular response in others, most notably in neuronal and endocrine cells. Several models have been proposed to explain these diverse actions of cAMP and G s -coupled receptors on ERK activation, both apparently involving in most cases the principal cAMP target, the cAMP-activated protein kinase (PKA) (6, 7). In particular, PKA-dependent ERK activation in HEK-293 cells by the ␤ 2 -adrenergic receptor (␤ 2 -AR), a prototypical G s -coupled receptor, has been extensively studied. Lefkowitz and coworkers (8) reported that cAMP-activated PKA phosphorylates the ␤ 2 -AR and thereby alters the coupling specificity of the receptor from G s to G i proteins. By this G protein "switching," the ␤ 2 -AR then apparently induces ERK activation by releasing G␤␥ dimers from the pertussis toxin (PTX)-sensitive G i proteins, followed by activation of the cytosolic tyrosine kinase c-Src, the GTPase Ras, and the MAP kinase kinase kinase, Raf-1. Meanwhile, it has been reported that the switching of ␤ 2 -AR from G s to G i proteins is controlled by ␤-arrestin, which recruits the cAMP-degrading phosphodiesterase 4 to the plasma membrane and thereby alters the activity state of PKA (9). In contrast, Schmitt and Stork (10) report that ERK activation by the ␤ 2 -AR in HEK-293 cells, although also PKA-and c-Src-dependent, is PTX-insensitive and thus apparently does not require ␤ 2 -AR switching to G i proteins, a finding recently confirmed by others using a PKAinsensitive ␤ 2 -AR mutant (11). Furthermore, Schmitt and Stork (10) show that ERK activation by ␤ 2 -AR is not mediated by Ras but by the related GTPase Rap1, activating the MAP kinase kinase kinase B-Raf, but not Raf-1. Interestingly, activation of the ␤ 2 -AR also resulted in Ras activation, but this receptor action was apparently independent of cAMP and PKA (10).

A series of eight substituted N-(4-(4-(2-halogenophenyl)piperazin-1-yl)butyl)-3-phenylacryl amide derivatives have been synthesized and screened for binding affinities at dopamine hD(2) and hD(3) receptors. All compounds have shown high to remarkable receptor affinities and some have led to distinct selectivity for D(3) receptors. Highest D(3)-receptor affinity has been observed for 3-(4-aminophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide (hD(3) K(i) 0.9 nM; hD(2) K(i) 17.4 nM). Selectivity ratio has been best for 3-(4-chlorophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide with a 56-fold preference for hD(3) versus hD(2). A functional activity test has been performed by a mitogenesis test for N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-3,3-diphenylacryl amide, which, surprisingly, has shown full agonist properties.

Pyrazine derivatives R 0550 N-(4-(4-(2-Halogenophenyl)piperazin-1-yl)butyl) Substituted Cinnamoyl AmideDerivatives as Dopamine D 2 and D 3 Receptor Ligands. -A series of cinnamoyl amides (I) (8 examples) is synthesized and evaluated for binding affinities at dopamine hD2 and hD3 receptors. All compounds show remarkable to high effects; some of them display distinct selectivity for D3 receptors. -(SAUR, O.; HACKLING, A. E.; PERACHON, S.; SCHWARTZ, J.-C.; SOKOLOFF, P.; STARK*, H.; Arch. Pharm. (Weinheim, Ger.) 340 (2007) 4, 178-184; Inst. Pharm. Chem., Johann Wolfgang Goethe-Univ., D-60439 Frankfurt/M., Germany; Eng.) -R. Staver 31-134

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