Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A₁ Adenosine Receptor Based on 2-Amino-3-(4′-Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene

Abstract

A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.

Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors

“…161 As a follow-up study, Baraldi and coworkers further examined the role of the C5-position on the AE activity in a second series of 4-neopentyl derivatives. 148 The presence of an phenylacetylene at the 5-position of the thiophene proved optimal for activity. As evidence, even at a low and finally led to a constant activity equivalent to that of the hydroiodide salts after 12 h. 162 Another putative factor complicating the interpretation of the different results might be the socalled probe-dependency, that is, the extent of allosteric action depending on the nature of the orthosteric ligand.…”

Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptor

“…The first A 1 AR PAM, PD81723, was identified by Bruns and coworkers in 1990 11 , 12 . Since then, a number of research groups have performed extensive structure-activity relationship (SAR) studies with the aim to improve the compound pharmacology and chemical properties 11 , 13 – 21 . Generally, the success of SAR studies has been limited due to a lack of structural basis for chemical modifications of the reference compound PD81723.…”

Safety issues of compounds acting on adenosinergic signalling

“…[138,139] They represent a highly selective way of agonism, for example highly selective A 1 AdR thiophene-based allosteric enhancer 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene. [140] Here, we have showed the complexity of adenosine signalling, especially the interference of diverse array of synthetic compounds with AdRs and enzymes involved in adenosine metabolism. There is still too little knowledge about the relation between adenosinergic signalling and emerging diseases, toxicological consequences, even developmental disabilities.…”

“…Due to dynamic, allosteric nature of AdRs (the most studied being the A 2A AdR), new allosteric enhancers represent a promising alternative to basic adenosine derivatives . They represent a highly selective way of agonism, for example highly selective A 1 AdR thiophene‐based allosteric enhancer 2‐amino‐3‐(p‐chlorobenzoyl)‐4‐substituted thiophene …”