Analogues of doxanthrine reveal differences between the dopamine D  1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

Cueva, J. P.; Chemel, B. R.; Juncosa, Jr. , J. I.; Lill, M. A.; Watts, V. J.; Nichols, D. E.

Abstract:

Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

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Article

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70032471

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Cueva, J. P.; Chemel, B. R.; Juncosa, Jr. , J. I.; Lill, M. A.; Watts, V. J.; Nichols, D. E.

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107

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English

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European Journal of Medicinal Chemistry

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Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines; 2012; Article; Journal; European Journal of Medicinal Chemistry; Cueva, J. P.; Chemel, B. R.; Juncosa, Jr. , J. I.; Lill, M. A.; Watts, V. J.; Nichols, D. E.