Doctor of Philosophy
Serotonin (5-HT) receptors represent a class of receptors involved in a variety of physiological processes including regulation of mood, perception, cognition, appetite, and heart function, and thus serve as drug targets of several drugs such as antipsychotic agents, hallucinogenic drugs, and appetite suppressant drugs. Due to the structural similarity of certain 5-HT receptor subtypes, particularly 5-HT2 receptors (5-HT2A, 5-HT2B receptors) determination and refinement of pharmacophore models of these receptor subtypes can greatly improve the therapeutic efficacy of drugs that target them.
The goals of this study were to define and/or refine existing pharmacophore models for 5-HT2A and 5-HT2B receptors. Investigation of 5-HT2A receptors involved analysis of a previously published pharmacophore for 5-HT2A receptors based on the structure of the atypical antipsychotic risperidone. Investigation of a 5-HT2A receptor agonist quipazine and its positional isomers/analogues also aided in the elaboration of 5-HT2A receptor binding. Finally, to determine structural requirements for 5-HT2B agonist action, a series of phenyl-substituted amphetamine analogues and a series of 4-substituted-2,5-dimethoxyamphetamines (DOX-type phenylisopropylamine compounds) were analyzed for their 5-HT2B receptor functional activity.
In the present study, a previously known pharmacophoric 5-HT2A antagonist compound was synthesized along with its N-propyl analogue. The pharmacophoric compound, along with several others in a series in which the piperidine substituent varies in both length and bulk, were screened across serotonin, dopamine, and adrenergic receptors to determine if high affinity and selectivity can be achieved for 5-HT2A receptors. The affinity screen revealed that, as the size and bulk of the piperidine substituent increases, affinity and selectivity for 5-HT2A receptors increased albeit with an accompanying increase in D2 receptor affinity – antagonism at D2 receptors is responsible for extrapyramidal stimulation (EPS) symptoms associated with several antipsychotics. Because D2 receptor affinity could not be abolished, it was determined that extending the chain size of the piperidine substituent is not an effective method for achieving more selective 5-HT2A antagonists.
Computational analysis of quipazine and its analogues was conducted to determine their binding modes at 5-HT2A receptor crystal structures. Higher affinity ligands 1-NP and 2-NP were found to bind in a distinct pocket relative to the lower affinity ligands quipazine and isoquipazine. It was predicted that the binding pocket occupied by 1-NP and 2-NP contains numerous hydrophobic amino acids and that hydrophobic interactions with these residues confer the high affinity for this class of compounds.
Finally, evaluation of 5-HT2B receptors involved analyzing several 5-HT2B ligands in a Ca2+-release assay to determine their functional activity. In particular, analogues of norfenfluramine (nFen) and DOB were analyzed and it was determined that the agonist activity of nFen is driven by hydrophobic interactions of its 3-CF3 substituent. To determine the SAR of related phenylisopropylamines at 5-HT2B receptors, a series of DOX analogues was analyzed for their functional activity. It was discovered that larger, more lipophilic 4-position halogens such as bromine (DOB) and iodine (DOI) are more accommodated than smaller less lipophilic halogens such as fluorine (DOF). Supporting the importance of a hydrophobic interaction with the 4-position substituent, DOPR and DOTB containing propyl and t-butyl 4-position substituents, respectively, produced potencies on par with that of DOI. These studies resulted in formulation of the first ever pharmacophore for agonist activity at 5-HT2B receptors.
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