MAPPING THE A-RING MOLECULAR AREA OF DOPAMINE RECEPTORS

Project: Research project

Project Details

Description

DESCRIPTION (Investigator's Abstract): The etiology of many debilitating
neurological disorders including Parkinson's Disease, Huntington's disease
and schizophrenia is associated with either an inadequate or excessive
stimulation of central dopamine receptors. While drug molecules which act
as dopamine agonists or antagonists may be clinically useful, the
therapeutic picture has been complicated with the recent discovery of
dopamine receptor sub-types, designated D1 and D2, which mediate distinct
behavioral and peripheral responses.Therapeutic dopamine receptor ligands
can only be maximally effective if they exhibit high receptor selectivity,
which demands the elucidation of the physico/chemical properties of their
binding sites. Aporphines are prototypical dopaminergic ligands but suffer
from a lack of selectivity. It is the overall goal of this project to
identify the physico/chemical nature of the region of the dopamine receptor
that binds ring A of aporphinic dopaminergic ligands in both D1 and D2
subtypes to assist in the design of therapeutic agents with higher margins
of clinical safety. To accomplish this goal: (1) eight novel
hexahydroaporphine molecules containing cyclohexyl or bicyclic A rings will
be synthesized in enantiomerically pure form. These molecules have been
designed to interact in an agonist mode with D1 and/or D2 subtypes. A
scheme which involves the acid-catalyzed cyclization of an appropriately
substituted benzyloctahydroisoquinoline has been designed to provide the
requisite aporphine 10,11-diol. Experience from preliminary studies in
which bicyclic 10-monophenolic analogs were generated will facilitate the
synthesis. (2) The affinity of each cyclohexyl and bicyclic molecule for
D1 and D2 receptors will be assessed through radio-ligand binding studies
and compared to its aromatic parent.Replacing the aromatic A ring of the
aporphinic parents with the cyclohexyl or bicyclooctyl systems will
increase hydrophobic bonding capabilities, while eliminating opportunity
for van der Waals binding, permitting an assessment of the relative
importance of each. In addition, the bicyclooctane system provides greater
molecular bulk which allows an assessment of the importance of steric
hindrance to A ring-receptor interaction.(3) Cyclohexyl and bicyclic
ligands exhibiting high affinity for receptors will be evaluated for D1 and
D2 agonist/antagonist activity utilizing biochemical indicators to
determine the importance of hydrophobic interactions in eliciting each type
of activity.
StatusFinished
Effective start/end date9/1/928/31/95

Funding

  • National Institute of General Medical Sciences

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