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 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 Derivatives where the thiourea functionality in the coupling region has been replaced by either amide or urea were synthesized as well.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.
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.
| Original language | English |
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| Qualification | Doctor |
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| Award date | 2006 Feb 3 |
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| ISBN (Print) | 91-628-6722-9 |
| Publication status | Published - 2006 |
Bibliographical note
Defence detailsDate: 2006-02-03
Time: 09:30
Place: Room K:B, Center for Chemistry and Chemical Engineering, Getingevägen 60, Lund Institute of Technology
External reviewer(s)
Name: Gundersen, Lise-Lotte
Title: Prof.
Affiliation: Department of Chemistry, Oslo 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
Free keywords
- COPD
- Asthma
- Capsazepine
- Bronchodilators
- Organic chemistry
- SAR studies
- Organisk kemi
