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Synthesis of serotonergic agents

Gharagozloo, Parviz; (1992) Synthesis of serotonergic agents. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Serotonin and its receptors have been the focus of intense research over the past decade. The identification of many serotonin receptor subtypes and the greater understanding of their physiological properties, has initiated many projects in search of potent and selective agents in the hope that novel therapeutic drugs may be identified. This is one such research project. This work has led to the discovery of several potent and selective 5-HT1A agents. This was achieved by structural modification of the lead compounds, β-blockers, aryloxypropanolamines. An historical review of the properties of serotonin, the classification and characterisation of serotonin receptors, and the structural requirements for activity at 5-HT1A and 5-HT1B receptors for many classes of compounds is presented. Structure-activity relationship for aryloxypropanolamines at β-adrenoceptors has also been discussed. Structural features which are known to be essential for β-adrenergic activity of pindolol, were modified and compounds with moderate affinities and selectivities for 5-HT1A receptors were obtained. Introduction of electron withdrawing substituents at the 6-position of the naphthalene ring of propranolol significantly reduced affinity at 5-HT1A and 5-HT1B receptors. Other structural modifications in this series, also yielded compounds with less affinity than propranolol. Novel analogues of 5-HT were also prepared and tested. These agents possessed reasonable affinities and selectivities for 5-HT1A receptors and displayed weak mixed agonistic and antagonistic activities at 5-HT1B receptors. Recent publication on structure-activity relationships for a number of propranolol analogues enabled us to design a novel series of compounds, analogous to cyanopindolol. These agents are potent and highly specific partial agonists at 5-HT1A receptors. All of the target analogues were prepared via the condensation reaction of epichlorohydrin or an aminoalkyl halide with a hydroxyindole or a substituted naphthol, followed by amminolysis. An effective procedure for the synthesis of 5-hydroxy-2-naphthoic acid, the key intermediate for the preparation of propranolol analogues, is described. The procedure for the preparation of other key intermediates in the synthesis of the analogues is also presented.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis of serotonergic agents
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10120385
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