Dopaminergic structure-activity relationships of 2-aminoindans and cardiovascular action and dopaminergic activity of 4-hydroxy, 5-methyl, 2-di-N-propylaminoindan (RD-211)

Abstract

Dopaminergic structure-activity relationships of 2-aminoindans were evaluated for their ability to inhibit responses to stimulation of cardioaccelerator nerves in cats. The major observations were as follows: 1) Unsubstituted di-n-propyl- and diethyl 2-aminoindan derivatives do not inhibit responses to stimulation of cardioaccelerator nerve, although previous studies identified stimulation of DA2-receptors. 2) 4-Hydroxy, 4,7-dimethoxy and 4-hydroxy, 5-CH3, -CH2OH or -H substitutions on selected indan derivatives produce dopaminergic activity in the cardioaccelerator nerve preparation. 3) 4-Hydroxy-2-di-n-propylaminoindan is stereoselective with the R-isomer being more potent than the S-isomer. One derivative, 4-hydroxy-5-methyl-di-n-propyl-2-aminoindan (RD-211) produced dose-dependent decreases in heart rate and mean arterial pressure. Larger doses also inhibited cardiac responses to stimulation of cardioaccelerator nerve in vivo and in isolated right atria of cats. All of the above responses were significantly inhibited by the dopamine-receptor antagonist sulpiride and not by the alpha2-adrenoceptor antagonist yohimbine. RD-211 also possesses high affinity for 5-hydroxytryptamine(1A) receptors as revealed by radioligand binding studies. Results suggest that RD-211 stimulates dopamine DA2-receptors and may also activate 5-hydroxytryptamine(1A) receptors, but is inactive at alpha2-adrenoceptors. RD-211 appears not to require metabolic activation even though it has the same chemical moiety as the aminotetralin homolog, which is a dopaminergic prodrug (5-hydroxy-6-methyl-2-di-n-propylaminotetralin).