Acyclic derivatives of adenine, known as highly effective nucleotide analogs with broad spectrum antiviral activity, were evaluated for potential cross-reactivity with adenylyl cyclases, a family of membrane-bound enzymes that share putative topologies at their catalytic sites with oligonucleotide polymerases and reverse transcriptases. A series of derivatives of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) inhibited a preparation of adenylyl cyclase derived from rat brain with IC(50) values that ranged from 66 microM (PMEA) to 175 nM for its diphosphate derivative (PMEApp) and mimics of it. PMEApp mimics included PMEAp(NH)p, PMEAp(CH(2))p, PMEAp(CX(2))p (X = fluorine, chlorine, or bromine), PMEAp(CHX)pp, and PMEAp(C(OH)CH(3)pp. The data suggest that inhibition of adenylyl cyclases may contribute to the therapeutic action of some of these or similar compounds or constitute part of their side effects in therapeutic settings.