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The α 1 -adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α 1 -adrenergic ligands, yet there is little information describing this drug class at the α 1 -adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α 1A - and α 1B -adrenergic receptors. The 9-aminoacridines increase the rate of [ 3 H]prazosin dissociation from the α 1A - and α 1B -adrenergic receptors and noncompetitively inhibit receptor activation by the endogenous agonist norepinephrine. The structurally similar compound, tacrine, which is a known allosteric modulator of the muscarinic receptors, is also shown to be a modulator of the α 1 -adrenergic receptors, which suggests a general lack of selectivity for allosteric binding sites across aminergic G protein-coupled receptor. Conjugation of two 9-aminoacridine pharmacophores, using linkers of varying length, increases the potency and efficacy of the allosteric effects of this ligand, likely through optimization of bitopic engagement of the allosteric and orthosteric binding sites of the receptor. Such a bivalent approach may provide a mechanism for fine tuning the efficacy of allosteric compounds in future drug design efforts.

Homobivalent Conjugation Increases the Allosteric Effect of 9-aminoacridine at the α1-Adrenergic Receptors

Homobivalent Conjugation Increases the Allosteric Effect of 9-aminoacridine at the α₁-Adrenergic Receptors