Enhanced D1 Affinity in a Series of Piperazine Ring Substituted 1-Piperazino-3-Arylindans with Potential Atypical Antipsychotic Activity

Article abstract of DOI:10.1021/jm00022a004

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-spiro-cyclopentyl).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 SKF 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1μmol/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 α₁ 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 piperazinering.Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10nM.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.