@article {Svenssonjpet.116.236372, author = {Kjell A Svensson and Beverly A Heinz and John M Schaus and James P Beck and Junliang Hao and Joseph H Krushinski and Matthew R Reinhard and Michael P Cohen and Sarah L Hellman and Brian G Getman and Xushan Wang and Michelle M Menezes and Deanna L Maren and Julie F Falcone and Wesley H Anderson and Rebecca A Wright and S Michelle Morin and Kelly L Knopp and Benjamin L Adams and Borys Rogovoy and Ilya Okun and Todd M Suter and Michael A Statnick and Donald R Gehlert and David L Nelson and Virginia L Lucaites and Renee Emkey and Neil W DeLapp and Todd R Wiernicki and Jeffrey W Cramer and Charles R Yang and Robert F Bruns}, title = {An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-in Mice without Causing Stereotypy or Tachyphylaxis}, elocation-id = {jpet.116.236372}, year = {2016}, doi = {10.1124/jpet.116.236372}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Allosteric potentiators amplify the sensitivity of physiological control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ. In HEK293 cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ~12\% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ~30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3-20 mg/kg p.o.) caused a robust (~10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30-240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958 and A-77636 showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for four days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared to direct-acting agonists.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2016/11/03/jpet.116.236372}, eprint = {https://jpet.aspetjournals.org/content/early/2016/11/03/jpet.116.236372.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }