Pharmacological properties of novel bicyclic isoquinoline analogs in isolated guinea pig atria, trachea and in human platelets: relationship to trimetoquinol.
1. Antiplatelet and beta-adrenoceptor activities of a set of secondary and tertiary N-methyl substituted amine analogs of trimetoquinol (TMQ, I and II, respectively) and 5,8-ethano-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquin oline (bicyclic isoquinoline compounds III and IV, respectively) were examined. 2. Compounds III and IV induced relaxations of guinea pig trachea which were blocked by propranolol whereas neither compound acted as an agonist nor antagonist of beta-adrenoceptors (chronotropy) in guinea pig atria. TMQ analogs (I and II) were agonists in both beta-adrenoceptor systems. 3. When tested in human platelets, compounds III and IV, like the TMQ analogs, blocked several inducers of the prostaglandin-dependent and -independent pathways, and the alpha 2-adrenoceptor-mediated pathway of platelet activation. 4. The bicyclic isoquinoline analogs (III and IV) possessed more selective beta 2-adrenoceptor stimulatory activity and equal or greater inhibitory activity against inducers of the prostaglandin-independent pathways of platelet function than the corresponding TMQ analogs (I and II). 5. These chemically novel lipophilic bicyclic compounds provide a new lead to the development of agents useful for the treatment of asthma and thrombotic disorders.
Division of Pharmacology, College of Pharmacy, Ohio State University Columbus 43210.
G
G
Shams
J
J
Fedyna
K J
KJ
Romstedt
A
A
Adejare
D D
DD
Miller
V F
VF
Roche
D R
DR
Feller
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010703:Phorbol Esters / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D014132:Trachea / Q000187:drug effects; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D010703:Phorbol Esters; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D011943:Receptors, Adrenergic, beta; D012701:Serotonin; D000001:Calcimycin; D014213:Tretoquinol