Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase
Abstract
Dihydrexidine (DHX), the first high-affinity D(1) dopamine receptor full agonist, is only 10-fold selective for D(1) versus D(2) receptors, having D(2) affinity similar to the prototypical agonist quinpirole. The D(2) functional properties of DHX and its more D(2) selective analog N-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D(2) receptors in rat striatum typical of D(2) agonists, binding to both high- and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D(2) receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D(2) receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D(2) sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D(2L) and D(2S) receptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed "functional selectivity") suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery.
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Development of functionally selective compounds that antagonize presynaptic D2 receptors while acting as agonists postsynaptically has been proven feasible.
“The development of such functionally-selective compounds has been proven to be feasible (Mottola et al., 2002) and is therefore a promising strategy for the treatment of addiction.”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Mottola et al., 2002
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- Authors
- Mottola, D. M., Kilts, J. D., Lewis, M. M., Connery, H. S., Walker, Q. D., Jones, S. R., Booth, R. G., Hyslop, D. K., Piercey, M., Wightman, R. M., Lawler, C. P., Nichols, D. E., & Mailman, R. B.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Pennsylvania State University (US)
- Pfizer (United States) (US)
- Purdue University West Lafayette (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 301
- Issue
- 3
- Pages
- 1166-1178
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2129352725
- Cited by
- 123
- References
- 82
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 8 · 2015: 11 · 2014: 9 · 2013: 4 · 2012: 11
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Update notices
- erratum (2002-07-01)
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH-53356, MH-40537, MH03327, MH-42705, R01MH040537, R01MH042705)
- National Institute on Drug Abuse (DA07244)
- National Institute of Environmental Health Sciences (ES-07126, T32ES007126)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD01130)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- functional selectivity, dopamine D2 receptor, dihydrexidine, dopamine D1 receptor agonist, autoreceptors, striatum, substantia nigra, adenylate cyclase, cAMP production, guanine nucleotides, receptor isoforms, quinpirole, dopamine agonists
- MeSH terms
- Adenylyl Cyclases, Animals, Binding, Competitive, Biological Availability, Corpus Striatum, Dopamine, Injections, Subcutaneous, Male, Phenanthridines, Pituitary Gland, Prolactin, Synaptic Membranes, Rats, Sprague-Dawley, Receptors, Dopamine D2, Dopamine Agonists, Rats
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