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SAR Studies of Capsazepinod Bronchodilators. The A-ring and the Coupling region

Dalence, Maria LU (2006)
Abstract
Bronchoconstriction is a hallmark in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Current therapies use bronchodilating agents in order to control the exacerbations produced by limited airflow and improve the quality of life of patients suffering from these diseases.



Capsazepine, a compound derived from the active principle of hot pepper (Capsicum annuum), capsaicin, was found in this study to relax the constriction induced by several constricting agents in human small airway smooth muscle in vitro. Assays were performed in order to unravel its mechanism of action. Mechanisms such as Beta2-adrenoreceptor agonism, muscarinic receptor antagonism, TRPV1 mediated mechanism and... (More)
Bronchoconstriction is a hallmark in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Current therapies use bronchodilating agents in order to control the exacerbations produced by limited airflow and improve the quality of life of patients suffering from these diseases.



Capsazepine, a compound derived from the active principle of hot pepper (Capsicum annuum), capsaicin, was found in this study to relax the constriction induced by several constricting agents in human small airway smooth muscle in vitro. Assays were performed in order to unravel its mechanism of action. Mechanisms such as Beta2-adrenoreceptor agonism, muscarinic receptor antagonism, TRPV1 mediated mechanism and inhibition of voltage operated calcium channels were excluded, suggesting the possibility of a novel mechanism of action.



Capsazepine derivatives (capsazepinoids) were synthesized. This thesis discusses the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepine (7-membered B-ring), 2,3,4,5-tetrahydro-1H-3-benzazepine (symmetrical 7-membered B-ring), 1,2,3,4-tetrahydroisoquinoline (6-membered B-ring) and isoindoline (5-membered B-ring) derivatives having different substitution patterns in the aromatic A-ring. Derivatives where the thiourea functionality in the coupling region has been replaced by either amide or urea were synthesized as well.



All derivatives synthesized were tested for its in vitro bronchorelaxing activity using human small bronchi (0.5-1.5 mm of diameter). The values of activity obtained were correlated with the structure of the compounds. The analysis was solely based on structural features since the target is not known. In addition, a conformational analysis of derivatives having 5, 6 and 7-membered B-rings was made in order to strengthen the structure-activity relationships found. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Gundersen, Lise-Lotte, Department of Chemistry, Oslo University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
COPD, Asthma, Capsazepine, Bronchodilators, Organic chemistry, SAR studies, Organisk kemi
pages
70 pages
publisher
Organic Chemistry, Lund University
defense location
Room K:B, Center for Chemistry and Chemical Engineering, Getingev├Ągen 60, Lund Institute of Technology
defense date
2006-02-03 09:30
ISBN
91-628-6722-9
language
English
LU publication?
yes
id
4f725e35-21f4-4cf1-a21f-785eb6a56c17 (old id 25767)
date added to LUP
2007-06-08 11:06:06
date last changed
2016-09-19 08:45:12
@misc{4f725e35-21f4-4cf1-a21f-785eb6a56c17,
  abstract     = {Bronchoconstriction is a hallmark in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Current therapies use bronchodilating agents in order to control the exacerbations produced by limited airflow and improve the quality of life of patients suffering from these diseases.<br/><br>
<br/><br>
Capsazepine, a compound derived from the active principle of hot pepper (Capsicum annuum), capsaicin, was found in this study to relax the constriction induced by several constricting agents in human small airway smooth muscle in vitro. Assays were performed in order to unravel its mechanism of action. Mechanisms such as Beta2-adrenoreceptor agonism, muscarinic receptor antagonism, TRPV1 mediated mechanism and inhibition of voltage operated calcium channels were excluded, suggesting the possibility of a novel mechanism of action.<br/><br>
<br/><br>
Capsazepine derivatives (capsazepinoids) were synthesized. This thesis discusses the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepine (7-membered B-ring), 2,3,4,5-tetrahydro-1H-3-benzazepine (symmetrical 7-membered B-ring), 1,2,3,4-tetrahydroisoquinoline (6-membered B-ring) and isoindoline (5-membered B-ring) derivatives having different substitution patterns in the aromatic A-ring. Derivatives where the thiourea functionality in the coupling region has been replaced by either amide or urea were synthesized as well.<br/><br>
<br/><br>
All derivatives synthesized were tested for its in vitro bronchorelaxing activity using human small bronchi (0.5-1.5 mm of diameter). The values of activity obtained were correlated with the structure of the compounds. The analysis was solely based on structural features since the target is not known. In addition, a conformational analysis of derivatives having 5, 6 and 7-membered B-rings was made in order to strengthen the structure-activity relationships found.},
  author       = {Dalence, Maria},
  isbn         = {91-628-6722-9},
  keyword      = {COPD,Asthma,Capsazepine,Bronchodilators,Organic chemistry,SAR studies,Organisk kemi},
  language     = {eng},
  pages        = {70},
  publisher    = {ARRAY(0x93c89d0)},
  title        = {SAR Studies of Capsazepinod Bronchodilators. The A-ring and the Coupling region},
  year         = {2006},
}