A_2B Adenosine Receptor Agonists: Synthesis and Biological Evaluation of 2‐Phenylhydroxypropynyl Adenosine and NECA Derivatives

Abstract

In the search for agonists for the elusive A_2B 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 A_2B 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, A_2A, A_2B, and A₃ adenosine receptors, showed that these modifications produced a decrease in potency at A_2B 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 A_2B subtype. Hence, (S)‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine [(S)‐PHPNECA] with EC₅₀ A_2B = 220 nM remains the most potent agonist at A_2B receptor reported so far.

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Keywords:

• Adenosine receptors
• A_2B adenosine receptor
• 2‐alkynyladenosine derivatives
• 2‐alkynylNECA derivatives

Acknowledgments

Supported by a grant from the Ministry of Research (COFIN, Grant no. 2001052834, 2001 and no. 200061553, 2002) and by the University of Camerino (Fondo di Ricerca di Ateneo).

Notes

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.