Date of Degree


Document Type


Degree Name





Wayne W. Harding


Shengping Zheng

Committee Members

Shengping Zheng

Adam Profit

Subject Categories

Medicinal-Pharmaceutical Chemistry | Organic Chemistry


5-HT2A, 5-HT2B, Aporphines, CNS, Molecular Docking, Nantenine


Aporphines are a group of tetracyclic alkaloids that belong to the ubiquitous tetrahydroisoquinoline family. The aporphine template is known to be associated with a range of biological activities. Aporphines have been explored as antioxidants, anti-tuberculosis, antimicrobial and anticancer agents. Within the Central Nervous Systems (CNS), aporphine alkaloids are known to possess high affinity for several clinically valuable targets including dopamine receptors (predominantly D1 and D2), serotonin receptors (5-HT1A and 5-HT7) and α adrenergic receptors. Aporphines are also inhibitors of the acetylcholinesterase enzyme – a clinical target for the treatment of Alzheimer’s disease. Considering the diverse profile of aporphine alkaloids at CNS receptors they can be considered as “privileged scaffold” for the design of CNS drugs.

The aporphine alkaloid nantenine is a 5-HT2A receptor antagonist and has moderate affinity for the 5-HT2A receptor. Selective 5-HT2A antagonists have therapeutic potential for the treatment of a number of neuropsychiatric disorders including depression, schizophrenia and sleep disorders. The aporphine core of nantenine serves as a valuable lead for the identification of selective 5-HT2A antagonists.

In order to understand the structural tolerance of the aporphine core required for 5-HT2A antagonism an exhaustive Structure Activity Relationship (SAR) study was designed.Accordingly, a diverse library of nantenine analogues was synthesized and evaluated for affinity at the 5-HT2A receptor. Results from the SAR studies demonstrate that the nitrogen atom of nantenine is required for affinity and that introduction of a phenyl ring at the C4 position is detrimental for 5-HT2A receptor affinity. At the C3 position, introduction of halogen atoms is beneficial for 5-HT2A antagonistic activity. Furthermore, a library of C3 analogues having hydrophobic substituents as well as ring D indole analogues is currently being evaluated for affinity at the 5-HT2A receptors. These compounds will further expand our understanding of the tolerance of the aporphine core required for 5-HT2A antagonism.

In order to rationalize the affinity of certain high affinity ligands, molecular docking studies were conducted. Selected compounds were docked into a homology model of the 5-HT2A receptor to extract information about possible binding modes. Based on results of these studies, it is concluded that the interaction of C3 halogenated aporphine analogues with Phe339/Phe340 residues might be responsible for their enhanced affinity. Information obtained from molecular docking studies is being utilized for design of advanced generations of analogues.

Finally, a novel series of flexible tris-(phenylalkyl)amines were synthesized and evaluated to test the importance of a rigid aporphine core as well as incorporation of N-phenylalkyl substituents. These compounds featuring a halogen substituent in ring C, were found to have high affinity and selectivity for the 5-HT2B receptor, with some of the compounds being more potent than the selective 5-HT2B antagonist SB200646. Results from this study indicate that ring C of these compounds is generally tolerant for halogen substitution. The synthetic feasibility of this newly identified template ( 4 high-yielding synthetic steps from commercially available materials) makes this scaffold attractive for the synthesis of larger libraries of analogs and promise for optimization of 5-HT2B affinity and selectivity.