Beta-adrenergic receptor and platelet inhibitory activities of a new series of trimetoquinol and related benzazepine analogs.
1. A series of dimethoxy and methylenedioxy analogs of trimetoquinol (TMQ) and structurally related 7-membered ring benzazepines (BA) were evaluated for their pharmacological effects in beta-adrenergic (atria, trachea) and thromboxane A2/prostaglandin H2 receptor systems (aorta, platelets). 2. Results show that both the 6,7-dihydroxy (catechol) moiety of trimetoquinol and an intact tetrahydroisoquinoline nucleus are essential for maintaining potent beta-stimulating and antithromboxane A2 activities. 3. By contrast, ring enlargement, as in the BA analogs, or masking of the catechol with dimethoxy or methylenedioxy functional groups enhanced the potency of inhibitors on thromboxane A2-independent activation of human platelets induced by bacterial phospholipase C (PLC). 4. The selective blockade of this pathway by these compounds suggests that they may represent a new and novel class of antiplatelet drugs.
Shams
G
G
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210, USA.
Romstedt
K J
KJ
Lust
L A
LA
Clark
M T
MT
Miller
D D
DD
Feller
D R
DR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D001552:Benzazepines; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010738:Type C Phospholipases; D014213:Tretoquinol