Abstract
BackgroundDopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists.MethodscAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R.ResultsAll tested agonists showed (almost) full agonism in both pathways.ConclusionsThe tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.
Highlights
Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines
Results cyclic adenosine mono phosphate (cAMP) In our previous studies the novel AMC compounds 11a, 12a and 12d bound with a high-affinity to the DA D2high receptor and were full agonists compared to DA itself; DA, 11a and 12a were potent, and 12d was a little more potent [19]
*pKi, pEC50 and Emax values are the average of at least two duplicate experiments with standard deviations (SD) values that were less than a third of the mean. †Parts published earlier in van Wieringen et al, 2014 [19]. ‡For IBZM no high-affinity state was detected; pKi value represents affinity for the total number of D2 receptors
Summary
Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Not all agonists activate the classic cyclic adenosine mono phosphate (cAMP) and the β-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. The D2R is a subfamily within the superfamily of Gprotein-coupled receptors (GPCRs) and contains several subtypes including some in the D2-like subfamily, the D2 (splice variants D2short (D2S) and D2long (D2L) [1]), D3 and D4 receptors [2] They primarily couple to the Gi/o type of G-proteins to inhibit the enzyme adenylyl cyclase in producing cyclic adenosine mono phosphate (cAMP) [2].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
