Wong, Kit Yee; (1997) Design and synthesis of 5-HT1A receptor ligands. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic amine known to function through a number of different 5-HT receptor subtypes. The 5-HT1A receptor subtype is implicated in conditions such as depression and anxiety. There are many examples of selective agonists for this receptor, although selective antagonists have only recently become available. Aryloxyalkylamine ?- adrenergic antagonists, such as pindolol and propranolol, are one of the few classes of ligands that exhibit antagonist activity at 5-HT1A receptors, although they are not selective. This thesis describes the synthesis and biological activity of a series of pindolol and propranolol analogues, with the aim of improving their 5-HT1A receptor affinities and selectivities. Modifications to the terminal amine substituents of these compounds were made and the effect of 7-substitution in the naphthalene ring was explored. These analogues possess high 5-HT1A versus ?-adrenergic receptor selectivities, although few compounds show significant 5-HT1A versus 5-HT1D receptor selectivity. In particular, the 7-CONH2 and 7-CO2Me substituted N,N- ethylbutylaminoethoxynaphthalenes were found to be potent agonists at the 5-HT1A receptor, having IC50 values of 3.3 and 5.2 nM respectively. Substitution of different groups in the 7-position of the naphthalene ring was found to have a profound effect on the 5-HT1A and 5-HT1D receptor affinities. Using the Hansch linear-free energy model, attempts were made to determine the relationships between the physicochemical nature of the substituents and their biological activities at these receptors. A multiple least squares linear regression procedure was used to generate several QSAR models. The models were analysed by statistical procedures to determine their validity and significance. Although the procedure did not yield a valid model for the 5-HT1A receptor affinities, good correlations were obtained for the 5-HT1D receptor affinities.

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