title: Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.
abstract: A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D016475:3T3 Cells; D018663:Adrenergic Agents / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018663:Adrenergic Agents; D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007189:Indans; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine