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′‐ethylcarboxamido group in the same compounds led to (R,S)‐N6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine and (S)‐N6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine, which did not show the expected increase in potency at A2B subtype. Hence, (S)‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine [(S)‐PHPNECA] with EC50 A2B = 220 nM remains the most potent agonist at A2B receptor reported so far. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.