Dopamine agonist activity of EMD 23,448.

EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED50 greater than 5.0 mg/kg i.p.); production of emesis in beagles (minimum effective dose = 81 micrograms/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses less than or equal to 50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for [3H]-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED50 value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the gamma-butyrolactone-induced increase in striatal dopa levels (ED50 = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+/-)-3-PPP.