Design and synthesis of 3-(benzimidazol-2-yl)propionic acids as thromboxane A2 receptor antagonists

A series of 3-​(benzimidazol-​2-​yl)​propionic acids substituted at the N1 nitrogen with Me and benzyl groups and at the C5 and C6 positions with chloro, methoxy, amino, hydroxyl groups were synthesized and tested as TXA2 receptor antagonists. None of the compds. showed any antiaggregating activity

The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist

We have characterized the in vitro pharmacological profile of the new potent and selective A2a adenosine receptor antagonist SCH 58261 [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine]. In binding studies on rat and bovine brain tissues, SCH 58261 showed affinity in the low nanomolar range at A2a adenosine striatal receptors and good A2a adenosine vs. A1 adenosine selectivity (about 50- to 100-fold in rat and bovine brain, respectively). SCH 58261 did not show affinity for either the A3 adenosine receptor or other receptors at concentrations up to 1 microM. Saturation experiments on rat A1 and A2a adenosine receptors indicated the competitive nature of the antagonism. SCH 58261 antagonized competitively the effects induced by the A2a adenosine-selective agonist CGS 21680 (2-[4-(2-carboxyethyl)-phenethyl-amino]-5'-N- ethylcarboxamidoadenosine) in two functional assays, such as inhibition of rabbit platelet aggregation and porcine coronary artery relaxation. Specifically, the compound showed pA2 values of 7.9 and 9.5, respectively. SCH 58261 (300 nM) failed to antagonize 5'-N-ethylcarboxamidoadenosine-induced vasorelaxation in the isolated guinea pig aorta, a response mediated by A2b adenosine receptors. Likewise, at the same concentration, the compound weakly inhibited the A1 adenosine-mediated negative chronotropic effect induced by 2-chloro-N6-cyclopentyladenosine in the isolated rat atria. These data show that SCH 58261 is a potent and selective non-xanthine A2a adenosine antagonist which has competitive properties in biological responses mediated by this receptor subtype. The compound is of interest for investigating the biological role of A2a adenosine receptors and deserves further attention to clarify the therapeutic potential of A2a antagonists

[(3)H]-SCH 58261 labelling of functional A(2A) adenosine receptors in human neutrophil membranes

1. The present study describes the direct labelling of A(2A) adenosine receptors in human neutrophil membranes with the potent and selective antagonist radioligand, [(3)H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4 triazolo[1,5-c]pyrimidine, ([(3)H]-SCH 58261). In addition, both receptor affinity and potency of a number of adenosine receptor agonists and antagonists were determined in binding, adenylyl cyclase and superoxide anion production assays. 2. Saturation experiments revealed a single class of binding sites with K(d) and B(max) values of 1.34 nM and 75 fmol mg(−1) protein, respectively. Adenosine receptor ligands competed for the binding of 1 nM [(3)H]-SCH 58261 to human neutrophil membranes, with a rank order of potency consistent with that typically found for interactions with the A(2A) adenosine receptors. In the adenylyl cyclase and in the superoxide anion production assays the same compounds exhibited a rank order of potency identical to that observed in binding experiments. 3. Thermodynamic data indicated that [(3)H]-SCH 58261 binding to human neutrophils is entropy and enthalpy-driven. This finding is in agreement with the thermodynamic behaviour of antagonists binding to rat striatal A(2A) adenosine receptors. 4. It was concluded that in human neutrophil membranes, [(3)H]-SCH 58261 directly labels binding sites with pharmacological properties similar to those of A(2A) adenosine receptors of other tissues. The receptors labelled by [(3)H]-SCH 58261 mediated the effects of adenosine and adenosine receptor agonists to stimulate cyclic AMP accumulation and inhibition of superoxide anion production in human neutrophils

Characterization of human A(2A) adenosine receptors with the antagonist radioligand [(3)H]-SCH 58261

1. We have characterized the binding of the new potent and selective antagonist radioligand [(3)H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, [(3)H]-SCH 58261, to human cloned A(2A) adenosine receptors. 2. In Chinese hamster ovary (CHO) cells transfected with the human cloned A(2A) receptor, [(3)H]-SCH 58261 specific binding (about 70%) was rapid, saturable, reversible and proportional to protein concentration. The kinetic K(D) value was 0.75 nM. Saturation experiments showed that [(3)H]-SCH 58261 labelled a single class of recognition sites with high affinity (K(D)=2.3 nM) and limited capacity (apparent B(max)=526 fmol mg(−1) protein). 3. Competition experiments revealed that binding of 0.5 nM [(3)H]-SCH 58261 was displaced by adenosine receptor agonists with the following order of potency: 2-hexynyl-5′-N-ethylcarboxamido-adenosine (2HE-NECA)>5′-N-ethylcarboxamidoadenosine (NECA)=2-phenylaminoadenosine (CV 1808)>2-[4-(2-carboxyethyl)-phenethylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680)>R-N(6)-phenylisopropyladenosine (R-PIA)⩾N(6)-cyclohexyladenosine (CHA)>S-N(6)-phenylisopropyladenosine (S-PIA). 4. Adenosine receptor antagonists inhibited [(3)H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943)>SCH 58261>xanthine amine congener (XAC)>(E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S)> 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)>theophylline. 5. Affinity values and rank order of potency of both receptor agonists and antagonists were similar to those previously obtained in human platelet and rat striatal membranes, except for CV 1808 which was more potent than CGS 21680. SCH 58261 was a competitive antagonist at inhibiting NECA-induced adenosine 3′ : 5′-cyclic monophosphate (cyclic AMP) accumulation in CHO cells transfected with human A(2A) receptors. Good agreement was found between binding and functional data. 6. Thus, the new antagonist radioligand is preferable to the receptor agonist radioligand [(3)H]-CGS 21680 hitherto used to examine the pharmacology of human cloned A(2A) adenosine receptors