Pharmacological assessments of potent A2A receptor antagonist IDPU (1-(7-imino-3-propyl-2,3-dihydrothiazolo[4,5-d]pyrimidin-6(7H)-yl)urea) in rodent model of haloperidol induced Parkinson like symptoms

Neurosci Lett. 2017 Apr 24:647:53-60. doi: 10.1016/j.neulet.2017.03.033. Epub 2017 Mar 20.

Abstract

A2A receptor antagonists emerged as potential candidate for management of Parkinson's disease. Earlier we had reported the therapeutic potential of 1-(7-imino-3-propyl-2,3-dihydrothiazolo[4,5-d]pyrimidin-6(7H)-yl) urea (IDPU) as A2A receptor antagonist. Herein, we have investigated the effect of IDPU in attenuation of haloperidol induced Parkinson like symptoms in rats. It has successfully restored hypo-locomotion induced by haloperidol and NECA. IDPU also displayed protective effect against oxidative stress induced by chronic haloperidol treatment in rats. The antidepressant activity of IDPU was determined in mice showed that it imperatively reduced depression like symptoms in well-established depression models viz. TST and FST. Additionally, IDPU was found to be a safe and non-toxic chemical entity in acute, sub-acute and neurotoxicity studies. In silico study of IDPU showed acceptable physicochemical parameters and in vitro screening exhibited satisfactory metabolic stability. This study clearly indicates that A2A receptor antagonist IDPU is able to ameliorate Parkinsonian symptoms without exerting any significant toxicity.

Keywords: A(2A) receptor antagonist; Catalepsy; Depression; IDPU; Oxidative stress; Toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / therapeutic use*
  • Adenosine A2 Receptor Antagonists / toxicity
  • Adenosine-5'-(N-ethylcarboxamide)
  • Animals
  • Antiparkinson Agents / therapeutic use*
  • Antiparkinson Agents / toxicity
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Female
  • Haloperidol*
  • Male
  • Mice
  • Motor Activity
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Parkinson Disease / psychology
  • Rats, Wistar
  • Receptor, Adenosine A2A / metabolism*
  • Thiazoles / therapeutic use*
  • Thiazoles / toxicity
  • Toxicity Tests, Acute
  • Toxicity Tests, Subacute
  • Urea / analogs & derivatives*
  • Urea / therapeutic use
  • Urea / toxicity

Substances

  • (1-(7-imino-3-propyl-2,3-dihydrothiazolo(4,5-d)pyrimidin-6(7H)-yl)urea
  • Adenosine A2 Receptor Antagonists
  • Antiparkinson Agents
  • Receptor, Adenosine A2A
  • Thiazoles
  • Adenosine-5'-(N-ethylcarboxamide)
  • Urea
  • Haloperidol