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

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 Derivatives where the thiourea functionality in the coupling region has been replaced by either amide or urea were synthesized as well.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.