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  2. An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

  • J Pharmacol Exp Ther. 2017 Jan;360(1):117-128. doi: 10.1124/jpet.116.236372.
Kjell A Svensson 1 Beverly A Heinz 2 John M Schaus 2 James P Beck 2 Junliang Hao 2 Joseph H Krushinski 2 Matthew R Reinhard 2 Michael P Cohen 2 Sarah L Hellman 2 Brian G Getman 2 Xushan Wang 2 Michelle M Menezes 2 Deanna L Maren 2 Julie F Falcone 2 Wesley H Anderson 2 Rebecca A Wright 2 S Michelle Morin 2 Kelly L Knopp 2 Benjamin L Adams 2 Borys Rogovoy 2 Ilya Okun 2 Todd M Suter 2 Michael A Statnick 2 Donald R Gehlert 2 David L Nelson 2 Virginia L Lucaites 2 Renee Emkey 2 Neil W DeLapp 2 Todd R Wiernicki 2 Jeffrey W Cramer 2 Charles R Yang 2 Robert F Bruns 2
Affiliations

Affiliations

  • 1 Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana (K.A.S., B.A.H., J.M.S., J.P.B., J.H., J.H.K., M.R.R., M.P.C., S.L.H., B.G.G., X.W., M.M.M., D.L.M., J.F.F., W.H.A., R.A.W., S.M.M., K.L.K., B.L.A., T.M.S., M.A.S., D.R.G., D.L.N., V.L.L., R.E., N.W.D., T.R.W., J.W.C., C.R.Y., R.F.B.); Chemical Diversity, Inc., San Diego, California (B.R., I.O.) svensson_kjell_a@lilly.com.
  • 2 Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana (K.A.S., B.A.H., J.M.S., J.P.B., J.H., J.H.K., M.R.R., M.P.C., S.L.H., B.G.G., X.W., M.M.M., D.L.M., J.F.F., W.H.A., R.A.W., S.M.M., K.L.K., B.L.A., T.M.S., M.A.S., D.R.G., D.L.N., V.L.L., R.E., N.W.D., T.R.W., J.W.C., C.R.Y., R.F.B.); Chemical Diversity, Inc., San Diego, California (B.R., I.O.).
Abstract

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.

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