Naphthobenzazepines and related compounds as conformationally-restricted probes of the dopamine D(1) receptor

Kitaw Negash, Purdue University

Abstract

In an effort to determine the spatial limits of the binding site for the $\beta$-phenyl moiety and the conformation of the ethylamine side chain in $\beta$-phenyldopamines, with respect to the dopamine D$\sb1$ receptor, we have undertaken the syntheses of the hitherto unknown 2-amino-1-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (22-30) and naphthobenzazepines 31-33. Phenylaminotetralins 44a and 44b were employed as common intermediates in the syntheses of these compounds. Also, 44b was utilized as an intermediate in a new approach to the syntheses of ($\pm$)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo (a) phenanthridine (dihydrexidine, 17a). The syntheses of 44a and 44b were accomplished using modifications of some earlier work by Riggs.$\sp{93}$ Intermediate 44a was obtained by a shorter and more facile route that would also be applicable to the syntheses of 44b. Radioligand binding studies of 22-30 showed that these compounds had virtually no affinity for the dopamine D$\sb1$ receptor. Conversely, dihydroxyphenylaminotetralins 23, 25, and 29 exhibited significant affinity for the dopamine D$\sb2$ receptor. This is an unusual finding for compounds having a $\beta$-phenyl moiety. The N-propyl-substituted catechol 29, especially showed a modest affinity (187 nM) and high selectivity (210-fold) for the D$\sb2$ versus D$\sb1$. Superimposition of energy-minimized structures of representative aminotetralin 25 and dihydrexidine showed that the $\beta$-phenyl moiety of 25 was nearly perpendicular to that of dihydrexidine, possibly explaining the attenuated affinity of 22-30 for the D$\sb1$ receptor. Naphthobenzazepines 31-33 showed virtually no affinity for either of the receptors. This finding might suggest that any further deviation of the orientation of the $\beta$-phenyl moiety from that of dihydrexidine is detrimental for D$\sb1$ agonist activity. The lack of D$\sb1$ antagonist activity in 32 and 33 could also be explained by the fact that these molecules incorporate the trans $\beta$-rotamer ethylamine side chain, as opposed to that of the gauche (cisoid) rotamer of the prototypic D$\sb1$ antagonist SCH 23390 and its conformationally restricted analog SCH 39166.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Organic chemistry|Biochemistry

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