PT - JOURNAL ARTICLE AU - Kjell A. Svensson AU - Beverly A. Heinz AU - John M. Schaus AU - James P. Beck AU - Junliang Hao AU - Joseph H. Krushinski AU - Matthew R. Reinhard AU - Michael P. Cohen AU - Sarah L. Hellman AU - Brian G. Getman AU - Xushan Wang AU - Michelle M. Menezes AU - Deanna L. Maren AU - Julie F. Falcone AU - Wesley H. Anderson AU - Rebecca A. Wright AU - S. Michelle Morin AU - Kelly L. Knopp AU - Benjamin L. Adams AU - Borys Rogovoy AU - Ilya Okun AU - Todd M. Suter AU - Michael A. Statnick AU - Donald R. Gehlert AU - David L. Nelson AU - Virginia L. Lucaites AU - Renee Emkey AU - Neil W. DeLapp AU - Todd R. Wiernicki AU - Jeffrey W. Cramer AU - Charles R. Yang AU - Robert F. Bruns TI - An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis AID - 10.1124/jpet.116.236372 DP - 2017 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 117--128 VI - 360 IP - 1 4099 - http://jpet.aspetjournals.org/content/360/1/117.short 4100 - http://jpet.aspetjournals.org/content/360/1/117.full SO - J Pharmacol Exp Ther2017 Jan 01; 360 AB - Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (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 orally) 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, A-77636, and dihydrexidine 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 4 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 with direct-acting agonists.