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. 2017 Jul 5;8(8):835-840.
doi: 10.1021/acsmedchemlett.7b00175. eCollection 2017 Aug 10.

Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression

Sujay Basu  1 , Dinesh A Barawkar  1 , Vidya Ramdas  1 , Minakshi Naykodi  1 , Yogesh D Shejul  1 , Meena Patel  1 , Sachin Thorat  1 , Anil Panmand  1 , K Kashinath  1 , Rajesh Bonagiri  1 , Vandna Prasad  1 , Ganesh Bhat  1 , Azfar Quraishi  1 , Sumit Chaudhary  1 , Amol Magdum  1 , Ashwinkumar V Meru  1 , Indraneel Ghosh  1 , Ravi K Bhamidipati  1 , Amol A Raje  1 , Vamsi L M Madgula  1 , Siddhartha De  1 , Sreekanth R Rouduri  1 , Venkata P Palle  1 , Anita Chugh  1 , Narayanan Hariharan  1 , Kasim A Mookhtiar  1
Affiliations

Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression

Sujay Basu et al. ACS Med Chem Lett. .

Abstract

Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).

Keywords: Parkinson’s disease; adenosine receptors; pharmacokinetics; rat liver microsomes.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of 9–33
Reagents and conditions: (i) ethanol amine, EtOH, 100–110 °C, 28 h; (ii) 4-nitrophenyl chloro formate, K2CO3, CH3CN, rt, 24 h; (iii) MeI, CH3CN, K2CO3, 60 °C, 16 h; (iv) NH2NH2·H2O, EtOH, 100–110 °C, 16 h; (v) R2-COOH, EDCI, HOBt, NMM, DMF, rt, 3 h; (vi) BSA, HMDS, 140–150 °C, 14 h; (vii) p-toluenesulfonyl chloride, pyridine, rt, 24 h; (viii) R1 = aryl piperazine, DIPEA, DMF, 80 °C, 16 h.
Figure 1
Figure 1
(A) Effect of compound 33 on haloperidol-induced catalepsy in rats. (B) Effect of compound 33 on potentiation of levodopa-induced contralateral rotations in 6-OHDA lesioned rats. *Significantly different as compared to l-DOPA, 4 mg/kg, IP alone group. (C) Effect of compound 33 in forced swim test (FST). (D) Effect of compound 33 in tail suspension test (TST) of mice. (E) Chronic effect of compound 33 in combination with l-DOPA or l-DOPA on abnormal involuntary movements (AIMs; dyskinesia) in 6-OHDA lesioned rats. All data represent mean ± SEM (n = 6–7). *Significantly different as compared to vehicle (* P < 0.05); vehicle: 0.5% Tween-80 + 0.5% CMC, q.s..
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