Interaction of the preferential D3 agonist (+)PHNO with dopamine D3-D2 receptor heterodimers and diverse classes of monoamine receptor: relevance for PET imaging.

Abstract

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D3 versus D2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD3 and hD2L receptors, (+)PHNO revealed high affinity at hD4.4 but not hD1 or hD5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT1A and h5-HT7. (+)PHNO behaved as a full agonist at hD4.4 and h5-HT1A receptors with potencies comparable to its actions at hD3 and hD2L receptors, and with less potency at 5-HT7 receptors. In binding assays with membranes derived from cells co-expressing hD3 and hD2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD3or hD2L receptors, suggesting that (+)PHNO promotes formation of hD3-hD2L heterodimers. Further, in cells co-expressing hD3 and hD2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD2L receptors. In conclusion, (+)PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.

• Authors: Francesco Petragnano, Irene Fasciani, Clotilde Mannoury la Cour, Benjamin di Cara, Gabriella Aloisi, Marco Carli, Shivakumar Kolachalam, Mario Rossi, Francesco Marampon, Marco Scarselli, Mark J Millan, Roberto Maggio
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 925 Pg. 175016 (Jun 15 2022) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 35545150 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Dopamine Agonists
• Oxazines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Adenylyl Cyclases
• Dopamine

Topics

• Adenylyl Cyclases
• Dopamine (metabolism)
• Dopamine Agonists (pharmacology)
• Oxazines
• Positron-Emission Tomography (methods)
• Receptors, Dopamine D2 (metabolism)
• Receptors, Dopamine D3 (metabolism)