SAR studies of Capsazepinoid Bronchodilators The B-ring and the C-region

Magnus Berglund

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Capsazepine and similar compounds, capsazepinoids, were shown to be general inhibitors of agonist (leukotriene D4, histamine, acetylcholine, prostaglandin D2) evoked constriction of human small airway preparations. The mechanism of action remains to be elucidated, but established bronchodilator principles, e.g. beta2-adrenoceptor agonism, as well as TRPV1 antagonism were shown to be less likely. From a systematic variation of the structure of capsazepine, divided into four regions, i.e. the fused catechol (A-ring), the fused 2,3,4,7-tetrahydro-1H-azepine (B-ring), the thiourea (coupling) and the 2-(4-chlorophenyl)ethyl (C-region), SAR:s were established. From this study 5,8-dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide, with a nearly tenfold higher potency compared to capsazepine, emerged. This compound was shown to be similarly potent, but more efficient than established bronchodilators, e.g. salbutamol and formoterol, in dilating human small airway preparations.

SAR findings concerning the B-ring and the C-region of capsazepine, revealed that a conformational constrain, i.e. a fused B-ring, is important to the activity. This ring should preferably be part of a 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol and should not be substituted. The C-region should include an aromatic moiety, without bulky substituents, and be linked to the thiourea with a short linker, e.g. methylene or ethylene. In addition the linker could be a ring fused with the benzene ring. The hydrophilicity of capsazepinoids could be increased, without loss of the activity, if the benzene ring in the C-region is replaced with pyridine. Conformational analysis supported the SAR:s suggested.

The attempts to replace the in vivo metabolically labile hydroxyl groups of the catechol moiety with other functional groups all resulted in loss of activity.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Centre for Analysis and Synthesis
Supervisors/Advisors
  • Sterner, Olov, Supervisor
Award date2006 Feb 17
Publisher
Print ISBNs91-628-6725-3
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-02-17
Time: 09:30
Place: Room K:B, Center for Chemistry and Chemical Engineering, Getingevägen 60, Lund Institute of Technology

External reviewer(s)

Name: Grøtli, Morten
Title: Associate Professor
Affiliation: Department of Chemistry, Medicinal Chemistry, Göteborg University

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The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)

Subject classification (UKÄ)

  • Organic Chemistry

Keywords

  • Organisk kemi
  • Organic chemistry
  • bronchodilator
  • Capsazepine
  • structure activity relationship

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