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.
Hackling
Anneke
A
Institut für Pharmazeutische Chemie, Johann Wolfgang Goethe-Universität, Marie-Curie-Strasse 9, 60439 Frankfurt am Main, Germany.
Ghosh
Robin
R
Perachon
Sylvie
S
Mann
André
A
Höltje
Hans-Dieter
HD
Wermuth
Camille G
CG
Schwartz
Jean-Charles
JC
Sippl
Wolfgang
W
Sokoloff
Pierre
P
Stark
Holger
H
D000818:Animals; D002460:Cell Line; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008934:Mitogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
C477197:4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide; D002934:Cinnamates; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D008024:Ligands; D008934:Mitogens; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013936:Thymidine