| dc.contributor.author | Li, Rongshi. | en_US |
| dc.date.accessioned | 2014-10-21T12:36:50Z | |
| dc.date.available | 1993 | |
| dc.date.issued | 1993 | en_US |
| dc.identifier.other | AAINN93697 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55385 | |
| dc.description | This thesis includes the study of diltiazem (DTZ) metabolites and the rational design of novel class of dibenzotricyclic calcium antagonists. | en_US |
| dc.description | DTZ is a calcium antagonist widely used in the treatment of cardiovascular disorders. DTZ is subject to significant first pass metabolism and is rapidly and extensively converted in humans to a variety of metabolites, several of which have potent pharmacological activities. Three newly discovered DTZ metabolites have recently been reported and tentatively identified as N,O-didemethylated DTZ (4), O-demethylated DTZ (5), and DTZ N-oxide (6). However, their identities were not confirmed since no authentic compounds were available. | en_US |
| dc.description | Eight DTZ metabolites have been successfully synthesized, three of which were synthesized for the first time, some requiring 12 sequential chemical reactions. All eight synthetic DTZ metabolites were fully characterized. The three new DTZ metabolites (4, 5 and 6) isolated from human urine are identical to the corresponding authentic compounds I synthesized as confirmed by spectroscopic and chromatographic methods. In vitro calcium antagonistic activities of all metabolites (except 6) were evaluated on hamster aorta. | en_US |
| dc.description | Attempts to find a new class of calcium antagonists with tissue selectivity have been made for more than a decade. Recently, a series of compounds with dibenzotricyclic systems (DBTs) were reported as a new class of calcium antagonists with tissue selectivity (Kurokawa, M. et al. J. Med. Chem. 1991, 34, 927-934). These DBTs may confer antianginal activity without an effect on blood pressure. Structure-activity relationships showed that calcium antagonistic activity increased with a decrease of the angle between the planes of the two benzene rings in DBTs. | en_US |
| dc.description | A number of dibenzothiazepinones and dibenzoxazepinones have been designed, assisted with molecular modeling. X-Ray and molecular mechanics calculations show that the DBTs in this study have smaller angles between the planes of the two benzene rings than the DBTs reported. As calcium antagonists, the DBTs synthesized in this study showed the potencies of their vasorelaxant activities to be comparable with that of DTZ at submicromolar concentration. Some dibenzothiazepinone derivatives also have anti-HIV activity. | en_US |
| dc.description | Effects of all the DBTs and DTZ metabolites 4 and 5 on adenosine uptake by erythrocytes were also studied. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 1993. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Chemistry, Pharmaceutical. | en_US |
| dc.subject | Health Sciences, Pharmacy. | en_US |
| dc.title | Study of diltiazem metabolites and rational design of novel calcium antagonists. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
