RDS-127 (2-DI-NORMAL-PROPYLAMINO-4,7-DIMETHOXYINDANE) - CENTRAL EFFECTS OF A NEW DOPAMINE RECEPTOR AGONIST

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 224  (1) , 161-170
Abstract
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 in order to determine their possible interaction with dopamine (DA) receptors. Nanomolar concentrations of all 3 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 .mu.M. APO was very active in causing contralateral turning behavior in rats with a 6-hydroxydopamine-lesioned substantia nigra (SN); RDS-127 was .apprx. 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 primarily produced 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 when using the in vivo .gamma.-butrolactone 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 [100% inhibitory dose] = 40 .+-. 10 nmol/kg i.v.). 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. 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.