The potential liabilities and advantages of drug promiscuity are a growing concern in drug development, and modulation of polypharmacology can be useful in drug optimization. Here, we have studied patterns of off-target receptor interactions, mostly at G protein-coupled receptors (GPCRs) in the �M range, of nucleoside derivatives that are highly engineered for nM interaction with adenosine receptors (ARs). Because of the considerable interest of using AR ligands for treating diseases of the CNS, we have utilized the Psychoactive Drug Screening Program (PDSP) for probing promiscuity of these adenosine/adenine congeners at over 50 diverse receptors, channels and transporters. The step-wise truncation of rigidified, trisubstituted (at N6, C2, and 5' positions) nucleosides revealed unanticipated interactions with numerous biogenic amine receptors, ion channels and transporters, with affinities up to the nM range. The unmasking of consistent sets of structure activity relationship (SAR) at novel sites suggested similarities between receptor families in molecular recognition. Extensive molecular modeling of the GPCRs affected suggested binding modes of the ligands that supported the patterns of SAR at individual receptors. The recognition patterns for different GPCRs were clustered according to which substituent groups were tolerated and which residues were involved in ligand recognition. Thus, some likely off-target interactions can be predicted for analogues of this set of substructures, and similar analyses could be performed for unrelated structural families for other GPCRs.

Structural probing of off-target receptor activities within a series of adenosine/adenine congeners

247th National Meeting (2014)

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