Selective dopamine D(1) receptor ligands: Synthesis of naphthisoquinolines and benzisoquinolines

Amjad M Qandil, Purdue University

Abstract

In an effort to assess the effect of changes of the accessory ring and the nitrogen in the trans-β-dopamine-β-ring pharmacophore, which is proposed to be the optimal pharmacophore for D1-agonist activity, this work reports the synthesis of a series of potential dopamine agonists substituted at the nitrogen and at different positions of the phenyl ring, as modifications to the structure of the potent D1 agonist 8,9-dihydroxy-2,3,7,11b-tetahydro-1H-naphth[1,2,3-de]isoquinoline (dinapsoline). Six members of this series have been synthesized, N-allyl-dinapsoline (1), N-n-propyl-dinapsoline (2), 6-methyl-dinapsoline (3), 4-methyl-dinapsoline (4), N-allyl-4-methyl-dinapsoline (5), and N-n-propyl-4-methyl-dinapsoline (6). The synthesis of compounds 1 and 2 used the same intermediates, and a route was developed that was much improved over the reported synthesis of dinapsoline. Nevertheless, this new approach was complicated by very poor yields at a key cyclization step that employed concentrated sulfinic acid. Attempts to improve this step failed. The synthesis of compounds 3–6 utilized similar intermediates. An important feature of this synthesis involved the optimization of the Suzuki cross-coupling conditions when using vinyl triflates and boronic acids. The synthesis of 3-phenyl benz[h]isoquinolines 7 and 8 was also attempted. However, the chemistry failed when attempts were made to attach the pyridine and the dimethoxyphenyl ring. Compounds 1–6 will be evaluated pharmacologically to test the effect of these structural modifications on D1 and D2 receptor binding affinity and on behavioral effects.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Organic chemistry|Pharmaceutical sciences

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