Synthesis and Biological Evaluation of 2-Amino-3-(4-Chlorobenzoyl)-4-[N-(Substituted) Piperazin-1-yl]Thiophenes as Potent Allosteric Enhancers of the A₁ Adenosine Receptor

Abstract

The synthesis and evaluation of a series of 2-amino-3-(4-chlorobenzoyl)-4-[4-(alkyl/aryl)piperazin-yl]thiophene derivatives as allosteric enhancers of the A 1-adenosine receptor are described. The nature of substituents on the phenyl ring tethered to the piperazine seem to exert a fundamental influence on the allosteric enhancer activity, with the 4-chlorophenyl 8f and 4-trifluoromethyl 8j derivatives being the most active compounds in binding (saturation and displacement experiments) and functional cAMP studies.

The Second Extracellular Loop of the Adenosine A1 Receptor Mediates Activity of Allosteric Enhancers

“…In addition, increasing the size of the fused ring at the 4-and 5-positions increases AE activity . More recent studies showed that large substituents at the 4-and 5-positions also enhance AE activity (Romagnoli et al, 2008;Aurelio et al, 2009). These observations provide two possible explanations to account for differences in the AE activity of ATL525 and PD 81,723: the ability of ATL525 to form additional A 1 R-AE interactions and an increased ability to trap agonists in the orthosteric binding pocket, thereby preventing exit from the receptor.…”

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

“…Under these circumstances, a preferable approach would be to selectively potentiate nicotinic receptor function through PAMs (Maelicke and Albuquerque, 1996;Krause et al, 1998). Likewise, potentiation of the effects of adenosine has been proposed to be beneficial in localized areas of oxygen deficit such as angina, myocardial infarction, and stroke (Fredholm, 2007;Romagnoli et al, 2008). In addition to cardiovascular disease, PAMs have also been postulated to be of value in the treatment of psychoses and cognitive disorders via potentiation of mGluR5-mediated responses (O'Brien et al, 2003).…”

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors

“…Larger R‐group substituents at the 4 and 5 positions of the thiophene ring were well tolerated in SAR studies . Compound 4 is a structurally‐related derivative of 3 that has been shown to have increased PAM activity (∼7 fold increase in B max ) compared to 2 in competition assays with the radioligand [ 3 H]CCPA . In comparing the predicted binding mode of 3 and 4 , the R‐group extension leading to improved potency is rationalized by complementary hydrophobic interactions with the hydrophobic patch on the receptor surface shown in Figure a.…”