Truncated Nucleosides as A(3) Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions

Abstract

C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane ((N)-methanocarba) ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleosides containing alkyl or alkylaryl groups at the N(6) position were low-efficacy agonists or antagonists of the human A(3)AR with high selectivity. Higher hA(3)AR affinity was associated with N(6)-methyl and ethyl (K(i) 3-6 nM), than with N(6)-arylalkyl groups. However, combined C2-phenylethynyl and N(6)-2-phenylethyl substitutions in selective antagonist 15 provided a K(i) of 20 nM. Differences between 4'-truncated and nontruncated analogues of extended C2-p-biphenylethynyl substitution suggested a ligand reorientation in AR binding, dominated by bulky N(6) groups in analogues lacking a stabilizing 5'-uronamide moiety. Thus, 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N(6) groups, but reduced efficacy in A(3)AR-induced inhibition of adenylate cyclase.

Chart 1. (N)-Methanocarba-adenosine Derivatives as Selective A₃AR Ligands (hAR Affinity in nM): Full Agonists in the 5′-N-Methyluronamide Series (1 and 3) and Truncated Nucleosides (2) That Act as A₃AR Antagonists and Partial Agonists, Including the Present Target Structures (4–21)

Scheme 1. Synthesis of Truncated (N)-Methanocarba-adenosine Analogues

Reagents: (i) 2-Iodo-6-chloropurine, Ph₃P, DIAD, THF, rt. (ii) R¹NH₂, Et₃N, MeOH, rt. (iii) Substituted HC≡C-Ph-R², Pd(PPh₃)₂Cl₂, CuI, Et₃N, DMF, rt. (iv) 50% TFA (aq.), MeOH:CH₂Cl₂ (3:1), rt.