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Peripheral dopamine receptors.

¹Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.

American Journal of Hypertension

|June 1, 1990

Summary

New research explores dopamine receptor subtypes (DA1 and DA2) and their structural requirements for agonist activity. Novel compounds challenge existing theories, suggesting a need for reevaluation of dopamine receptor pharmacology.

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Area of Science:

Pharmacology
Neuroscience
Molecular Biology

Background:

The existence of two peripheral dopamine receptor subtypes, DA1 and DA2, has been proposed since 1979.
Distinct potency orders for agonists and selective antagonists have been identified for DA1 and DA2 receptors.
The mechanisms by which cyclic AMP modulation by DA1 and DA2 receptors leads to vascular relaxation remain unclear.

Purpose of the Study:

To investigate the DA1 and DA2 agonist activities of novel chemical structures, CY 208,243 and dihydrexidine.
To examine the structural requirements for DA1 and DA2 receptor agonist activity.
To challenge and reexamine current views on dopamine receptor subtype pharmacology.

Main Methods:

In vivo dog models were used to determine agonist potency orders for DA1 and DA2 receptors.
Selective antagonists (SCH 23390 for DA1, domperidone and (S)-sulpiride for DA2) were employed.
The effects of novel compounds (CY 208,243 and dihydrexidine) on DA1 and DA2 receptors were assessed.

Main Results:

Novel structures, CY 208,243 and dihydrexidine, exhibit DA1 and DA2 agonist activities.
Structural modifications, such as adding a benzene moiety to ergoline and benzoquinoline, resulted in DA1 agonist activity.
These modifications rendered molecules inactive at the DA2 receptor and reduced the requirement for hydroxyl groups for DA1 activity.

Conclusions:

The findings suggest that current understanding of structural requirements for DA1 and DA2 agonist activity needs revision.
Novel compounds provide new insights into dopamine receptor subtype pharmacology.
Further research is warranted to reexamine and refine the structural models for dopamine receptor interactions.

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