Studies directed toward the synthesis and evaluation of some substituted 10 -aminomethyl-9,10 -dihydroanthracenes as conformationally restricted analogues of beta-phenyldopamine
Abstract
In an effort to define further the geometry of the phenyl-accessory binding region of the dopamine D1 receptor and to assess the relative importance of side-chain conformation to agonist activity, we have undertaken the synthesis of a series dopamine agonists based on 10-aminomethyl-9,10-dihydroanthracene as conformationally restricted analogues of $\beta$-phenyldopamine. Molecular modeling studies indicated that the $\beta$-phenyl moiety in these compounds, which is constrained by means of a methylene bridge, adopts a conformation approximately $-$30$\sp\circ$ to 35$\sp\circ$ from coplanarity with the catechol ring. The series also embodies the range of side-chain conformations from a rigidified gauche rotameric conformation, through a freely rotating one, to a rigidified trans-$\beta$ rotamer. Two members of this series, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr (10,4a,4-cd) azepine, 1, and 10-aminomethyl-1,2-dihydroxy-9,10-dihydroanthracene 2, have been synthesized through a common intermediate, 10-aminomethyl-1,2-dimethoxy-9,10-dihydroanthracene. Synthesis of 8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth (1,2,3-de) isoquinoline from the same key intermediate was attempted but failed late in the synthetic scheme at the key Bischler-Napieralski cyclization step. Synthesis of the corresponding series of monohydroxydihydroanthracenes as potential dopamine antagonists was also attempted. However, chemistry similar to that used for the dihydroxy compounds failed at a key Friedel-Crafts cyclization step. Radioligand displacement experiments for 1 and 2 showed both compounds to have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. This attenuation of affinity could be due to improper orientation of the $\beta$-phenyl moiety, as compared to SKF 38393, or to an inability to attain the nitrogen to oxygen distance required for optimal receptor recognition.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology|Organic chemistry|Neurology
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