The main hypothesis under consideration is to establish whether the proposed modifications of trimetoquinol (TMQ) will produce agents which are highly potent and selective for subtypes of beta- adrenergic and thromboxane A2 (TXA2) receptor systems. Our studies will emphasize evaluation of newly synthesized TMQ analogs on pharmacological receptors in lung (beta 2), cardiovascular (beta 1), platelets (TXA2, aggregation, alpha) and smooth muscle, (TXA2, tone, tau) systems. Using stereoisomers and analogs of TMQ, we plan to search for compounds which interact selectively with different subtypes of beta2-adrenergic (skeletal muscle versus tracheal muscle) and thromboxane A2 (platelet versus vascular smooth muscle) receptors. Based on our previous work we have divided our synthetic objectives with TMQ analogs into three areas: 1) Synthesis of reversible agonists and antagonists including (a) optical isomers of fluorinated TMQ analogs that have shown selective beta 2 agonist and TXA2 antagonist properties, (b) analogs of TMQ that should have lowered phenolic pKa values and higher beta 2/beta 1-selectivity, and (c) cyclopropane analogs of TMQ for gaining insight into conformational requirements for beta 2-agonist and TXA2 antagonist activities; 2) Synthesis of optically active radioligands for characterizing subtypes of TXA2 and beta-adrenergic receptor binding sites; and 3) Synthesis of affinity and photoaffinity labels that should allow us to probe various binding sites on beta- adrenergic and TXA2 receptors. These compounds will be tested for their 1) potency as agonists or antagonist in tracheal, atrial, and skeletal muscle preparations; and 2) potency and specificity as antagonists of TXA2 mediated platelet aggregation and vascular smooth muscle contraction. Development of highly selective beta 2-adrenergic agonists for the treatment of respiratory disorders is desirable since the most frequently encountered side effects of these agents include tachycardia, tremors, and metabolic abnormalities. In recent years, a significant separation of undesirable cardiac stimulation from beneficial bronchodilation has been accomplished; however, to date, no separation of beta 2-adrenergic effects on skeletal muscle (tremor) from bronchodilation has been observed. The use of TXA2 receptor antagonists as probes will aid in the delineation of the biological role of this mediator in humans; and such agents should be useful in the treatment of vascular and thrombotic disorders commonly associated with coronary heart diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022533-08
Application #
3336920
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Pharmacy
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Nikulin, Victor I; Rakov, Igor M; De Los Angeles, Joseph E et al. (2006) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diols as novel affinity and photoaffinity probes for beta-adrenoceptor subtypes. Bioorg Med Chem 14:1684-97
Konkar, A A; Nikulin, V I; De Los Angeles , J et al. (2001) Biochemical activities of trimetoquinol analogs at human beta(1)- and beta(3)-adrenergic receptors. Pharmacology 62:45-55
Mehta, R C; Salazar-Bookaman, M M; Fertel, R H et al. (2000) Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human beta-adrenoceptors. Biochem Pharmacol 59:517-29
Zheng, W; Nikulin, V I; Konkar, A A et al. (1999) 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: novel selective beta3-adrenoceptor agonists. J Med Chem 42:2287-94
Konkar, A A; Vansal, S S; Shams, G et al. (1999) Beta-adrenoceptor subtype activities of trimetoquinol derivatives: biochemical studies on human beta-adrenoceptors expressed in chinese hamster ovary cells. J Pharmacol Exp Ther 291:875-83
Christoff, J J; Bradley, L; Miller, D D et al. (1997) Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity. J Med Chem 40:85-91
Shams, G; Romstedt, K J; Lust, L A et al. (1997) Beta-adrenergic receptor and platelet inhibitory activities of a new series of trimetoquinol and related benzazepine analogs. Gen Pharmacol 28:323-30
Romstedt, K J; Lei, L P; Feller, D R et al. (1996) Differential eudismic ratios in the antagonism of human platelet function by phenoxy- and thiophenoxyacetic acids. Farmaco 51:107-14
Konkar, A A; Fraundorfer, P F; Fertel, R H et al. (1996) Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes. Eur J Pharmacol 305:63-71
De Los Angeles, J E; Nikulin, V I; Shams, G et al. (1996) Iodinated analogs of trimetoquinol as highly potent and selective beta 2-adrenoceptor ligands. J Med Chem 39:3701-11

Showing the most recent 10 out of 32 publications