Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the α6∗ subtype

Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6∗ neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure–activity relationship are discussed in the context of the design of small molecules targeting smoking cessation. Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure–activity relationship are discussed in the context of the design of small molecules targeting smoking cessation.