Synthesis and investigation of the β-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol

• Published in: Journal of medicinal chemistry 1986-02, Vol.29 (2), p.181-185
• Main Authors: CLARK, M. T, CHANG, J, NAVRAN, S. S, HUZOOR-AKBAR, MUKHOPADHYAY, A, AMIN, H, FELLER, D. R, MILLER, D. D
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - pharmacology; Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - pharmacology; Animals; Blood Platelets - metabolism; Chemistry; Exact sciences and technology; Female; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; In Vitro Techniques; Isoquinolines - pharmacology; Male; Organic chemistry; Phosphatidylinositols - metabolism; Platelet Aggregation - drug effects; Preparations and properties; Structure-Activity Relationship; Tretoquinol - pharmacology; Type C Phospholipases - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00152a003

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.