Aporphines, 21. (1,2) Dopaminergic activity of aporphine and benzylisoquinoline derivatives. Synthesis of 8-hydroxyaporphines and 1-(hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinolines.

The synthesis and physical properties of 8-hydroxyaporphine (3a) and 8-hydroxy-N-n-propylnoraporphine (3b) are described. The replacement of the rigid aporphine ring system by the more flexible benzyltetrahydroisoquinoline moiety, still containing all the necessary substitutents of the potent dopamine agonist N-n-propylnorapomorphine (1b) (NPA), resulted in the synthesis of 1-(3,4-dihydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (4). Analogous to 4,1-(4-hydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (5) was synthesized for a direct comparison with the biological activity of the corresponding 10-hydroxyaporphine (2). All compounds synthesized were evaluated as salts of their racemates. In animals with unilateral 6-OHDA lesion of the nigrostriatal pathway, (-)NPA and 2 caused dose-dependent contralateral circling behavior although activity was greatly reduced for the monohydroxylated aporphine 2. 3b,4, and 5 were inactive at doses of 0.25-4.0 mg/kg sc. Compounds 2 and 3b exhibited very weak activity in the stereotype tests in comparison to the response obtained with apomorphine and (-)-NPA. 4 and 5 failed to induce any sterotyped response. These compounds were also investigated for their ability to stimulate locomotor activity following direct injection into the nucleus accumbens. (-)-NPA induced a modest increase in activity but apomorphine completely failed to elicit a locomotor responses and antagonized the effect induced by dopamine. 2,3b, 4 and 5 neither enhanced locomotor activity on direct injection into the nucleus accumbens nor antagonized the hyperactivity response to intraacumbens dopamine when administered peripherally. On direct injection into the caudate-putamen only apomorphine induced stereotyped biting; (-)-NPA, 2, 3b, 4, and 5 were inactive. The differential activity of the aporphine derivatives in these tests strongly supports the possible existence of different types of dopamine receptors within the extrapyramidal and mesolimbic systems. The present studies confirm that the flexible benzylisoquinolines 4 and 5 do not adopt the active dopamine conformation and that the rigid aporphines, preferably containing hydroxyl functions at the 10 or 11 positions, are of greater importance in eliciting potent dopamine agonist activity.