Microwave-Assisted Synthesis and Adenosine Receptor Binding Studies of Some Novel Triazolo, Imidazolo and Pyrimido pyrazolopyrimidines
Raghu Prasad Mailavaram
Department of Pharmaceutical Chemistry, Shri Vishnu College of Pharmacy,West Godavari District, Andhra Pradesh, India
Abstract:
Adenosine receptors (ARs) classified as A1, A2A, A2B and A3 subtypes, belong to the superfamily of G-protein coupled receptors (GPCRs) have emerged as potential drug targets and play significant role in a number of varied biological functions. In particular, the A2A ARs are present with high density in striatum, nucleus accumbens, olfactory tubercles and globus pallidus pars externa in rat and human brain and found to be colocalised with D2 receptors. Adenosine A2A receptors modulate the release of GABA in the striatum, which appears to regulate the activity of medium spiny neurons. By reducing GABA output, A2A antagonism helps to restore normal function in the basal ganglia following dopamine depletion. Thus, A2A receptor antagonists may be a useful treatment for neurodegenerative movement disorders such as Parkinson's and Huntington's disease, dystonias such as restless leg syndrome and dyskinesias such as those caused by prolonged use of neuroleptic and dopaminergic drugs.
Recently a series of triazolothienopyrimidines has been reported from our lab as adenosine A1 receptor antagonists at µM ranges and none of them showed affinity towards A2A ARs upto 1µM. Thus, a novel series of Triazolopyrazolo yrimidines Imidazolo pyrazolopyrimidines and pyrimidopyrazolopyrimidines has been synthesized (by utilizing MORE Chemistry) as bioisosteres of previously reported triazolothienopyrimidines and screen for their binding affinities and selectivity towards adenosine receptors in vitro (radioligand binding studies).
In Imidazolo and Pyrimido series the propyl derivative showed selective affinity towards A2a and in triazolo series all the compounds showed selective affinity towards A2a receptors at micromolar ranges which confirm the hypothesis proposed. Further optimization of the lead is in progress.
Keywords: Adenosine receptors, More chemistry, Heterofused pyrazolopyrimidines
