Hughes, G.A.; (2005) Novel, potent antagonists of capsaicin. Doctoral thesis , University of London.

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Abstract

The aim of this project was to explore and refine the conformational rationale for the activity of capsazepine (CPZ) as a blocker of the ion channel TRPV1 (transient receptor potential vanilloid type 1), by the synthesis and biological evaluation of further conformational constrained capsaicin analogues. The resolution of the stereoisomers of Af-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquino-line 29, Af-(4-chlorophenethylthio-carbamoyl)-6,7-dihydroxy-3-methyl-1,2,3,4-tetra-hydroisoquinoline 30 and N-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1,3-dimethyl-1,2,3,4-tetrahydroiso-quinoline 31 by stereoselective synthetic methodology is described, and some of the more unusual and interesting mechanisms are discussed. The novel asyrnmetric chemistry described includes the separation of the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by crystallisation with the enantiomers of mandelic acid, the use of sodium triacetoxyborohydride in the stereoselective reduction of 6,7-dimethoxy-l,3-dimethyl-3,4-dihydroiso-quinoline 171, to give the cw-diastereomers of 6,7-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 44, and the novel stereoselective route to the trans-diastereomers of 6,7-dimethoxy-l,3-dimethyl-l,2,3,4-tetrahydroisoquinoline 44 from the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by the Michael addition of A-benzyl-2-(3,4-dimethoxyphenyl)-l-methylethylamine 155 to ethynyl-4-tolylsulfone 150, followed by TFA-mediated cyclisation, single electron reductive desulfonylation and palladium-catalysed hydrogenolysis. The results of investigations into the conformational behaviour of the resolved stereoisomers of 29, 30 and 31 by techniques of NMR spectroscopy and molecular modelling, the evaluation of their biological activity at the rat and human orthologues of the ion channel TRPV1, and the attempted correlation of the two sets of data, with respect to the published conformational rationale for the activity of CPZ, are also described.

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