Khalaf, Yasmin Salman Abdul Husain Salman; (1990) Synthesis and structure activity studies of novel H3-receptor histamine antagonists. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes various approaches to the design and synthesis of potential H3- receptor histamine antagonists. The ultimate aim is to provide the basis for the design of a non-toxic, brain-penetrating compound which could be used as a prototype drug for investigative clinical studies in humans. Novel compounds were synthesized and submitted for testing as potential antagonists in vitro on rat cerebral cortex. The more active compounds were tested further, in vivo. The results, in terms of Kj or EC50 values were used as a guide in making further modifications of structures derived from compounds existing in the literature. The published selective H3 antagonist, N-cyclohexyl-4-(4 -imidazolyl)-!-piperidine carbothioamide (thioperamide) was used as a lead. In order to try to improve brain penetration, it was desirable to remove the imidazole group altogether, or replace it with a less hydrogen-bonding group. To this end the imidazole group was removed and the 4- piperidine position substituted with functional groups of differing polarities. The imidazole group was replaced with 2-pyridine, and the 3-(2-piperidinyl)pyridine isomer was also prepared. A significant loss of activity was observed for all these compounds. Another approach was to open up the piperidine ring in thioperamide, thus investigating the effect of increased flexibility on the molecule. This led to a drop in activity which was restored by methylating the sulphur atom. The potential toxicity of the thiocarbonyl group in thioperamide, was avoided by the synthesis of some esters and amides of urocanic acid. The p-nitrophenyl ester seemed to indicate a direction dependent dipolar interaction with the receptor. A set of amines was also prepared, one following up the p-nitro effect, and two exploring the omission of the imidazole group, this time with the retention of antagonistic activity. A number of ethyl-imidazol-4-yl isothioureas, with a range of n-alkyl and a cyclohexyl group substituted on the isothiourea nitrogen atoms, showed a progression from an antagonist as potent as thioperamide through to an agonist. Omitting the imidazole group from the most potent isothiourea antagonist, resulted in loss of activity. S-(2-(2-Pyridinyl)ethyl)isothiourea proved to be a partial agonist, while the propyl side chain analogue was an antagonist. Some analogous isoureas were prepared. Two novel synthetic schemes were developed, for the starting materials 2-(4- piperidinyl)pyridine and 3-(imidazol-4-yl)propylamine. Thus, an indication of the structure activity behaviour of antagonists at the H3 receptor has been established.

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