AbstractThe use of nicotine and tobacco products is highly addictive. The dopaminergic system plays a key role in the initiation and maintenance of nicotine intake. Dopamine D1‐like receptor blockade diminishes nicotine intake in rats with daily short (1 h) access to nicotine, but little is known about the effects of dopamine receptor antagonists or agonists on nicotine intake in rats with intermittent long (23 h) access. Because of the extended access conditions and high nicotine intake, the intermittent long access procedure might model smoking and vaping better than short access models. We investigated the effects of the dopamine D1‐like receptor antagonist SCH 23390 and the D1‐like receptor agonist A77636 on nicotine intake in male rats with intermittent short or long access to nicotine. The rats self‐administered nicotine for 5 days (1 h/day) and were then given 15 intermittent short (1 h/day) or long (23 h/day) access sessions (3 sessions/week, 0.06 mg/kg/inf). The D1‐like receptor antagonist SCH 23390 decreased nicotine intake to a similar degree in rats with short or long access to nicotine. The D1‐like receptor agonist A77636 induced a greater decrease in nicotine intake in the rats with long access to nicotine than in rats with short access. Treatment with A77636 induced a prolonged decrease in nicotine intake that lasted throughout the dark and light phase in the long access rats. These findings indicate that blockade and stimulation of D1‐like receptors decrease nicotine intake in an intermittent long access animal model that closely models human smoking and vaping.

01 Dec 2020·Journal of PsychopharmacologyQ3 · MEDICINE

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats

Q3 · MEDICINE

Article

Author: Demars, Fanny ; Lavergne, Francis ; Desormeaux, Cleo ; Jay, Therese M ; Davenas, Elisabeth

Background: Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. Aims: This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. Methods: Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. Results: During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. Conclusions: The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.

01 Jan 2017·The Journal of Pharmacology and Experimental Therapeutics

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

Article

Author: Wright, Rebecca A ; Maren, Deanna L ; Nelson, David L ; Falcone, Julie F ; Knopp, Kelly L ; Adams, Benjamin L ; Emkey, Renee ; Anderson, Wesley H ; Yang, Charles R ; Getman, Brian G ; Statnick, Michael A ; Cohen, Michael P ; Hao, Junliang ; Menezes, Michelle M ; Beck, James P ; Suter, Todd M ; Heinz, Beverly A ; Wiernicki, Todd R ; Krushinski, Joseph H ; DeLapp, Neil W ; Gehlert, Donald R ; Schaus, John M ; Okun, Ilya ; Morin, S Michelle ; Hellman, Sarah L ; Bruns, Robert F ; Wang, Xushan ; Cramer, Jeffrey W ; Reinhard, Matthew R ; Lucaites, Virginia L ; Rogovoy, Borys ; Svensson, Kjell A

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 K_b 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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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 2	US	Abbott Laboratories (Philippines), Inc.	-
Alzheimer Disease	Preclinical	GB	The University of Manchester	01 Jul 2012

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