Receptor Regulatory Properties Evident in the Molecular Similarity of β‐Adrenergic Receptor Ligands and Adenosine Triphosphate

Abstract

A degree of structural similarity is sometimes apparent between molecules that induce or antagonize pharmacologic responses and those responsible for effector action. Ligands selective for histamine receptors, for example, relate to purine nucleotide structure. Furthermore, histamine shows structural similarity to the nitric oxide synthetase substrate, arginine. Acetylcholine also initiates cell responses by binding to a guanine nucleotide-coupled receptor protein and activates the enzyme nitric oxide synthetase. Muscarinic receptor ligands are here compared with purine nucleotide and arginine structures. Relative configurations of acetylcholine, muscarinic agonists, muscarinic antagonists and guanosine triphosphate (GTP) show similarity in their relative configurations. The quaternary nitrogen, ester and carbonyl oxygen atoms in low-energy conformers of acetylcholine, superimpose on primary nitrogen and oxygen atoms of the a-phosphate group in GTP with a high degree of fit. The quaternary or tertiary nitrogen and negatively charged atoms in muscarinic agonists and antagonists show the same fit to the guanine nucleotide. In a similar low-energy conformer of acetylcholine, the same atomic groups relate to the minimum energy conformer of arginine; oxygen atoms in acetylcholine superimpose on nitrogen atoms in the guanidinum group of arginine on the basis of charge. A pharmacophore common to acetylcholine and other muscarinic ligands relates to regulator and substrate molecules involved in signal transduction at muscarinic receptors and nitric oxide generation.