Motor inhibition induced by aporphine derivatives in the mouse

Abstract

Abstract The ability of some aporphine and benzylisoquinoline derivatives to inhibit mouse spontaneous locomotor activity at low doses, and at higher doses to have a reduced motor inhibitory effect, was used to determine whether motor inhibitory and facilitatory potentials could be dissociated, and the optimal structure required to cause these behavioural changes. Ability to displace [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-naphthalene [3H]ADTN from its binding sites in rat striatal tissue was used as a broad measure of the abilities of the test compounds to bind to the ‘dopamine receptor’. The order of potency for ‘low dose’ inhibition of mouse spontaneous locomotion was (1) (-)N-n-propylnorapomorphine>(2) apomorphine > (3) (-)2,10,11-trihydroxy-N-n-propylnoraporphine > (4) (-)2,10,11-trihydroxyaporphine > (5) f-10,11-dihydroxy-N-(hydroxy-ethyl)noraporphine > (6) norapomorphine > (7) (±)10-hydroxy-N-n-propylnoraporphine > (8) 1-(3,4-dihydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroiso- quinoline. The latter two compounds were only weakly active and (±)8-hydroxy-N-n-propylnoraporphine and 1-(4-hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline were inactive. The reduction in motor inhibitory effect as dose of agonist was increased (indicative of facilitation of locomotion) was only observed with compounds 1 and 2, other compounds (3 and 4) caused non-specific changes which interfered with motor performance or the doses required were so large as to render testing impractical (5,6,7 and 8). The potent motor inhibitory actions of compounds 1–4 were antagonized by pretreatment with spiperone but not with prazosin or yohimbine. Specific binding of 2·0nM [3H]ADTN was displaced by nanomolar concentrations of (±)-ADTN and aporphine derivatives. Isoapomorphine and the two benzylisoquinoline derivatives were ineffective at 10−6M. The optimal structure for those derivatives examined was shown in all tests to be (-)N-n-propylnorapomorphine.