Abstract

This proposal examines the hypothesis that norepinephrine and related phenylethylamines (isoproterenol, epinephrine, etc.) can interact with a functional inhibitory site in isolated guinea-pig ileum distinct from currently defined alpha- and beta- adrenoceptors. The research objective is to characterize this putative adrenoceptor with regard to agonist and antagonist profiles. Quantitative pharmacological experiments are planned to measure pA2 values for competitive antagonists, the sensitivity of the putative site to irreversible antagonists, and agonist potency ratios, affinities, and efficacies. Characterization of the putative adrenoceptor in isolated guinea- pig ileum will lead to similar experimentation in isolated guinea- pig atria, rat atria, rabbit rectococcygeus muscle, rat stomach fundus, and rat vas deferens. (Evidence exists that an adrenoceptor, distinct from defined alpha- and beta-subtypes, exists in these tissues). The research project represents a basic science, pharmacological approach, to effector receptor classification and characterization. The results may have relevance to both physiological mechanisms and novel drug development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039621-04
Application #
3296768
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Project Start
1989-07-01
Project End
1992-01-31
Budget Start
1990-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Syntex (USA), Inc.-Research Division
Department
Type
DUNS #
City
Palo Alto
State
CA
Country
United States
Zip Code
94304

  Publications

Waikar, M V; Hegde, S S; Ford, A P et al. (1993) Pharmacological analyses of endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H- benzimidazole-1-carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat esophagus and ileum of J Pharmacol Exp Ther 264:654-61
Baxter, G S; Clarke, D E (1992) Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus. Eur J Pharmacol 212:225-9
Taneja, D T; Clarke, D E (1992) Evidence for a noradrenergic innervation to ""atypical"" beta adrenoceptors (or putative beta-3 adrenoceptors) in the ileum of guinea pig. J Pharmacol Exp Ther 260:192-200
Blue Jr, D R; Clarke, D E (1992) Slow off-rate of prazosin accounts for deviations from competitive antagonism in the isolated perfused kidney of rat. Gen Pharmacol 23:815-21
Baxter, G S; Craig, D A; Clarke, D E (1991) 5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae. Naunyn Schmiedebergs Arch Pharmacol 343:439-46
Blue, D R; Bond, R A; Adham, N et al. (1990) Antagonist characterization of atypical beta adrenoceptors in guinea pig ileum: blockade by alprenolol and dihydroalprenolol. J Pharmacol Exp Ther 252:1034-42
Bond, R A; Ornstein, A G; Clarke, D E (1989) Unsurmountable antagonism to 5-hydroxytryptamine in rat kidney results from pseudoirreversible inhibition rather than multiple receptors or allosteric receptor modulation. J Pharmacol Exp Ther 249:401-10
Taylor, S S; Bubis, J; Toner-Webb, J et al. (1988) CAMP-dependent protein kinase: prototype for a family of enzymes. FASEB J 2:2677-85