On the ability of N-chloroethyl aporphine derivatives to cause irreversible inhibition of dopamine receptor mechanisms

Abstract

Abstract The potential dopamine inhibitory properties of (-)N-(2-chloroethyl)-norapomorphine [(-)NCA], (-)N-(hydroxyethyl)norapomorphine [(-)NHA], (-)N-(2-chloroethyl)-norapocodeine[(-)NCC] and 6-[2-bis-(2-chIoroethyl)-amino]acetyl-11-acetoxy-2-hydroxy-10-methoxynoraporphine (I) were assessed in behavioural (ability to antagonize apomorphine climbing, stereotypy and circling after unilateral electrolesions of the striatum in the mouse, ability to initiate circling/asymmetry alone or after challenge with apomorphine when injected unilaterally into the striatum of rat) and biochemical (ability to inhibit the binding of [3H] (-)N-n-propylnorapomorphine, 3H-NPA, to rat striatal homogenates) tests. (-) NCA, 10–20 mg kg−1 s.c., antagonized apomorphine climbing for a period of 5 days, the response recovering to control values by the 7th day. 10 mg kg−1 s.c. (-)NHA, (-)NCC or I failed to modify apomorphine climbing. Similarly, 2–4 mg kg−1 s.c. (-)NCA caused a long-lasting inhibition of apomorphine circling in the mouse (up to 5 days) whilst (-)NHA, (-)NCC and I were inactive. (-)NCA (10–40 μg) (but not (-)NHA, (-)NCC or I) also caused ipsilateral circling/asymmetry when injected unilaterally into the striatum of rat: this effect was enhanced by apomorphine. However, all agents, including (-)NCA, failed to consistently modify apomorphine stereotypy in the mouse. Non-labelled (-)NPA, (-)NCA and (-)NHA were shown to inhibit the ‘specific’ binding of 3H-NPA to rat striatal homogenates; (-)NCC and I were ineffective. A single washing removed the (-)NHA inhibition whilst repeated washing caused only a modest reversal of the inhibition afforded by (-)NCA. It is concluded that N-chloroethylation in the aporphine series can abolish dopamine agonist action and confer a long-lasting dopamine antagonist potential.