DETQ
| Identifiers | |
|---|---|
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C22H25Cl2NO3 |
| Molar mass | 422.35 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
DETQ is an experimental drug which acts as a positive allosteric modulator of the Dopamine receptor D1. It increases the D1-mediated response to endogenous dopamine levels, and was developed as a potential treatment for Parkinson's disease.[1][2][3][4][5]
Chemogenetic sensitivity tuning
A significant challenge in dopamine imaging is the detection of low-level tonic signals, which often fall below the affinity threshold of standard genetically encoded biosensors like dLight. Recent developments in chemogenetics have introduced a method to "tune" sensor sensitivity using DETQ, a potent and selective positive allosteric modulator (PAM) of the dopamine D1 receptor.
Because many dopamine sensors (such as dLight1.3b) are engineered using a human D1 receptor scaffold, DETQ can stabilize the receptor's active conformation when dopamine is bound. This results in a significant left-shift in the EC50 and up to an 8-fold increase in dopamine sensitivity (e.g., from 2 µM to 244 nM).[6]
Crucially, DETQ exhibits a 30-fold lower affinity for rodent D1 receptors compared to the human-derived biosensor. This differential affinity allows researchers to temporarily "turn up the gain" on imaging signals in vivo without significantly altering the subject's endogenous behavior or physiology. This approach is particularly effective for resolving subtle, behavior-evoked phasic events and baseline tonic variations in brain regions with sparse dopaminergic innervation, such as the prefrontal cortex.[6]
See also
References
- ^ Svensson KA, Heinz BA, Schaus JM, Beck JP, Hao J, Krushinski JH, et al. (January 2017). "An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis". The Journal of Pharmacology and Experimental Therapeutics. 360 (1): 117–128. doi:10.1124/jpet.116.236372. PMC 5193077. PMID 27811173.
- ^ Bruns RF, Mitchell SN, Wafford KA, Harper AJ, Shanks EA, Carter G, et al. (January 2018). "Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders". Neuropharmacology. 128: 351–365. doi:10.1016/j.neuropharm.2017.10.032. PMID 29102759.
- ^ Svensson KA, Hao J, Bruns RF (2019). "Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders". Neuropsychotherapeutics. Advances in Pharmacology. Vol. 86. San Diego, Calif.: Elsevier. pp. 273–305. doi:10.1016/bs.apha.2019.06.001. ISBN 978-0-12-816668-0. PMID 31378255.
- ^ Meltzer HY, Rajagopal L, Matrisciano F, Hao J, Svensson KA, Huang M (April 2019). "The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice". Behavioural Brain Research. 361: 139–150. doi:10.1016/j.bbr.2018.12.006. PMID 30521930.
- ^ Rajagopal L, Huang M, Mahjour S, Ryan C, Elzokaky A, Svensson KA, et al. (February 2024). "The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux". Behavioural Brain Research. 459 114766. doi:10.1016/j.bbr.2023.114766. PMID 38048913.
- ^ a b Labouesse M, Wilhelm M, Kagiampaki Z, Yee A, Fava T, Patriarchi T (2024). "A chemogenetic approach for dopamine imaging with tunable sensitivity". Nature Communications. doi:10.1038/s41467-024-49442-3.