Dissertations, Theses, and Capstone Projects

Date of Degree

6-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Wayne Harding

Committee Members

Akira Kawamura

Shengping Zheng

Sanjai Pathak

Sushmeet Singh

Subject Categories

Biochemistry | Organic Chemicals

Keywords

Dopamine, Serotonin, Apomorphine, Nantenine, 5-HT7AR, D1, SAR at 5-ht7A

Abstract

Aporphine alkaloids, belonging to the isoquinoline class of compounds, have been investigated as a potential source of ligands for Central Nervous System (CNS) receptors. Previous research indicates that the aporphine scaffold may be manipulated to synthesize selective ligands for serotonin and dopamine receptors. Novel aporphine alkaloids containing C10 nitrogen substitutions were synthesized, and their affinities were evaluated at serotonin (5-HT1A, 5-HT1B, 5-HT2A, 5-HT7A) receptors and dopamine (D1, D2, D3, D4, and D5) receptors. Two series of racemic aporphine compounds with C10 nitrogenous functionalities were synthesized and analyzed at the aforementioned receptors. The first series of aporphine alkaloids contain C10 nitro, amine, amide, and methanesulfonamide motifs. Compounds in this C10 monosubstituted series displayed higher affinity at 5-HT1AR and 5-HT7AR and lacked affinity at 5-HT1BR and 5-HT2AR. This series contained compounds with an N6-methyl group and compounds with and N6-propyl group. The N6-methyl substituted C10 nitrogen functionalized aporphine analogs had higher binding affinities at 5-HT7AR versus 5-HT1AR. In contrast the N6-propyl sub-set of compounds exhibited a reversal of this selectivity. Compound 103a was the most potent compound and behaved as an antagonist at 5-HT7AR (Ki = 4.5 ± 0.6 nM, IC50 = 1.25 μM), with 10-fold selectivity over 5-HT1AR (Ki = 49 ± 6.3 nM). These monosubstituted analogs lacked significant binding among all dopamine receptor subtypes. C10 analogs with a benzofused aminothiazole moiety showed higher affinity and selectivity for serotonin receptors as compared to the C10 monosubstituted compounds. These compounds displayed high binding affinities for 5-HT1AR and 5-HT7AR; analogs containing an N6-methyl substitution favor binding at 5-HT7AR. Among the benzofused aminothiazole analogs compound 108a had the best binding affinity at 5-HT7AR (Ki = 6.5±0.8 nM) and functions as an antagonist (IC50 = 0.26 μM). These benzofused aminothiazole analogs also lacked affinity for dopamine receptors. Unlike analogs in the C10 monosubstituted subset, compounds with the benzofused aminothiazole moiety with an N6-methyl substitution displayed moderate affinity for 5-HT1BR. The second series of compounds contained a C1,2,10-trisusbtitution pattern on the aporphine core. The 1,2,10-trisusbtituted series of compounds as a group displayed weak binding affinity at 5-HT1AR and considerably higher binding affinity at 5-HT1BR. These compounds provided moderate affinity at 5-HT2AR and 5-HT7AR. At dopamine receptors, most of the trisubstituted series of compounds failed to show affinity towards D5 receptors suggesting a lack of tolerability at D5R receptors for C10 N substituted aporphines with moderate to low affinity at D1R, thus attaining D1R versus D5R selectivity. Compound 128e was the most potent D1R ligand (Ki = 58 nM) and lacked binding affinity at all other dopamine receptor subtypes. Compounds 103a, 108a, and 128e have been identified as three new lead compounds with promising pharmacodynamic properties for further tool and pharmaceutical optimization.

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