Synthesis of novel dopaminergic ligands: A bioisosteric approach

Russell Alan Grubbs, Purdue University

Abstract

This research describes the development of a new strategy for discovering novel dopaminergic compounds by utilizing two routes described previously. These routes were to rigidify the elements of the trans-β-dopamine-β-phenyl pharmacophore with methylene linkages and to substitute the elements of this pharmacophore with bioisosteric groups. The new strategy is a hybrid approach where the methylene linkages are replaced with bioisosteric ether linkages. Three series of compounds were designed and synthesized from the full dopamine D1 agonists dihydrexidine (2) and dinapsoline ( 3). The syntheses of these compounds involved Suzuki cross-coupling reactions, lithiations, enolate formation, ether syntheses, and isoquinoline syntheses and transformations. The ether bioisostere of dinapsoline that was named dinoxyline (5) was shown to be a full D1 agonist (EC50 = 30 nM) with approximately equal affinity for D1 (Ki = 7 nM) and D2 (Ki = 6 nM) receptors. Dinoxyline (5) also has high affinity for D3 (K i = 5 nM) and D4 (Ki = 43 nM) receptors. A ring-expanded analogue of dinoxyline (8) was synthesized that had little affinity (Ki > 1,000 nM) for the dopamine receptors tested. This result was surprising because a similar ring expanded analogue of dinapsoline (13) was able to bind to dopamine receptors. The ether analogue of dihydrexidine was named O-dihydrexidine (O-DHX; 9) and had low affinity (Ki > 1,000 nM) for the dopamine receptors tested. In order to develop further conclusions about these compounds, the N-allyl and N-propyl compounds were synthesized and their affinity for dopamine receptors measured. N-Alkylation did not increase affinity of dinoxyline for D2-like receptors as had been previously described for dihydrexidine (2) and dinapsoline (3). In addition, methyl groups were appropriately added to dinoxyline (5) and dinapsoline (3) to mimic the steric bulk of dihydrexidine's (3) 7,8-ethano bridge. These compounds were designed to determine the steric requirements for this region of the D 1 and D2 receptors. A detailed SAR study of the target compounds is presented.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Organic chemistry|Pharmacology

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