N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands.

The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity. Molecular modeling studies supported the structural development. Pharmacophore models for dopamine D(2) and D(3) receptor ligands were developed from their potentially bioactive conformation and were compared in order to get insight into molecular properties of importance for D(2)/D(3) receptor selectivity. For the 72 compounds presented here, an extended and more linear conformation in the aliphatic or aryl spacers turned out to be crucial for dopamine D(3) receptor selectivity. Structural diversity in the aryl moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar D(3) receptor affinity, which was optimized with more rigid aryl acrylamide derivatives. Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (K(i) (hD(3)) = 0.5 nM; K(i) (hD(2L)) = 76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel radioligand as a pharmacological tool for various D(3) receptor-related in vitro and in vivo investigation.

N-(4-(4-(2-Halogenophenyl)piperazin-1-yl)butyl) substituted cinnamoyl amide derivatives as dopamine D2 and D3 receptor ligands.

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.

Dopamine D3 receptor ligands with antagonist properties.

The dopamine D(3) receptor has been recognized to play an important role in the molecular mechanisms of various neuropsychiatric disorders. The development of new dopamine D(3) receptor selective antagonists is premised on the potentially improved therapeutic treatment of psychosis like schizophrenia. Partial agonists at dopamine D(3) receptors are supposed to be beneficial when administered to drug abusers or in Parkinson's disease. The structural basis for most compounds is at least a basic, aryl-substituted alkanamine part with an alkyl moiety, which in many compounds forms a spacer to another aryl residue. Structural variety among the amine moiety includes aminotetralins, tetrahydroisoquinolines, isoindoles, benzazepines, and aminoindans, as well as pyrrolidines, pyrroles, and 4-phenylpiperazines. Various ways for lead optimization are shown in different classes of compounds. Promising ligands with high D(3) receptor affinity often lack sufficient selectivity or display deficits in the required in vivo parameters. Structure-activity relationships for dopamine D(3) receptor antagonists and partial agonists are discussed here, along with the outlook for their potential therapeutic application.

Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands.

Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.