RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane): central effects of a new dopamine receptor agonist

Apomorphine (APO), 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) and 2-di-n-propylamino-5,8-dimethoxytetralin (JMC-181) were examined on a variety of biochemical and pharmacological assays to determine their possible interaction with dopamine (DA) receptors. Nanomolar concentrations of all three compounds displaced [3H]APO from specific high-affinity binding sites in rat striatal membrane preparations, while higher concentrations were required to displace [3H]spiperone or [3H]rauwolscine. APO caused a concentration-dependent increase in the ability to stimulate postsynaptic DA receptors associated with adenylate cyclase (D1-sites) in the carp retina, whereas RDS-127 or JMC-181 were inactive in concentrations up to 300 microM. APO was very active in causing contralateral turning behavior in rats with a 6-hydroxydopamine lesioned substantia nigra (SN); RDS-127 was approximately 8 times less potent in producing contralateral rotations and JMC-181 was inactive. RDS-127 produced biphasic, dose-related changes in rat spontaneous locomotor activity similar to that reported for APO. The locomotor stimulant effects of RDS-127 were 3 times more potent and 4 times greater in duration than that induced by APO. JMC-181 produced primarily sedation in the doses tested. APO, RDS-127 and JMC-181 were active in inhibiting the accumulation of dopa in the caudate nucleus and olfactory tubercle using the in vivo gamma-butyrolactone procedure; 5-hydroxytryptophan accumulations were not altered significantly. RDS-127 was 7 times more potent than APO in inhibiting dopa accumulation in the caudate nucleus and equipotent to APO in the olfactory tubercle. Dopa accumulation was weakly inhibited by JMC-181. When single unit extracellular action potentials were recorded from purported DA-containing neurons in the SN, RDS-127 decreased the firing of neurons in the pars compacta of SN (ID100 = 40 +/- 10 nmol/kg i.v.). In contrast, firing of units in the pars reticulata of SN were not altered or increased in response to RDS-127. The biochemical electrophysiological and behavioral effects of RDS-127 were blocked or reversed by DA receptor antagonists. These data indicate that RDS-127 is significantly more selective than APO in preferentially activating DA autoreceptors as opposed to the postsynaptic DA receptors in the nigrostriatal pathway. The possibilities of designing potent, long acting, nonergot, noncatechol-containing DA receptor agonists are discussed.