Development of specific dopamine D-1 agonists and antagonists
Abstract
To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo (a,d) cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo (1,2) cyclohepta (3,4,5-d,e) isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand binding data, $\rm IC\sb{50}$ of compound 11 for displacement of $\sp3\rm H$-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of $\sp3\rm H$-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology
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