ABSTRACT
A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential dual adenosine A1 and A2A receptor antagonists. The majority of the synthesised compounds exhibited promising dual affinities, with A1Ki values ranging from 0.175 to 10.7 nM and A2AKi values ranging from 1.58 to 451 nM. The in vivo activity illustrated for 3-(2-amino-6-phenylpyrimidin-4-yl)phenyl morpholine-4-carboxylate (4c) is indicative of the potential of these compounds as therapeutic agents in the treatment of Parkinson's disease, although physicochemical properties may require optimisation.
Subject(s)
Adenosine A1 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/chemistry , Pyrimidines/chemistry , Binding Sites , Carbamates/chemistry , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kinetics , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Pyrimidines/metabolism , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists.
Subject(s)
Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A1 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Animals , Catalepsy/chemically induced , Catalepsy/prevention & control , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Haloperidol , HeLa Cells , Humans , Male , Molecular Docking Simulation , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the monoamine oxidase inhibitory properties of this versatile scaffold, a series of furanochalcones were synthesized. The results demonstrate that these furan substituted phenylpropenones exhibited moderate to good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. The most active compound, 2E-3-(5-chlorofuran-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one, exhibited an IC50 value of 0.174 µM for the inhibition of MAO-B and 28.6 µM for the inhibition of MAO-A. Interestingly, contrary to data previously reported for chalcones, these furan substituted derivatives acted as reversible inhibitors, while kinetic analysis revealed a competitive mode of binding.
