A2B Adenosine Receptor Agonists: Synthesis and Biological Evaluation of 2‐Phenylhydroxypropynyl Adenosine and NECA Derivatives.

Abstract

In the search for agonists for the elusive A2B adenosine receptor subtypes, 2‐phenylhydroxypropynyl‐5′‐N‐methylcarboxamido adenosine (PHPMECA, 14), 2‐phenylhydroxypropynyl‐5′‐N‐propylcarboxamido adenosine (PHPPECA, 15), and N 6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine (19) were synthesized on the basis that introduction of alkynyl chains in 2‐position of adenosine derivatives resulted in reasonably good A2B potency compared to NECA [see N 6‐ethyl‐2‐phenylhydroxypropynyl adenosine (5) EC50 = 1,700 nM and 2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamido adenosine (PHPNECA, 8) EC50 = 1,100 nM, respectively]. Radioligand binding studies and adenylyl cyclase assays, performed with recently cloned human A1, A2A, A2B, and A3 adenosine receptors, showed that these modifications produced a decrease in potency at A2B receptor, as well as a general reduction in affinity at the other receptor subtypes. On the other hand, the contemporary presence of an ethyl substituent in N 6‐position and of a 4′‐et...