Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Abstract

The activation of heteromeric and homomeric nicotinic acetylcholine receptors was studied in Xenopus laevis oocytes to identify key structures of putative agonist molecules associated with the selective activation of homomeric ␣7 receptors. We observed that selectivity between ␣7 and ␣4␤2 was more readily obtained than selectivity between ␣7 and ␣3␤4. Based on structural comparisons of previously characterized selective and nonselective agonists, we hypothesize at least three chemical motifs exist that, when present in molecules containing an appropriate cationic center, could be associated with the selective activation of ␣7 receptors. We identify the three distinct structural motifs based on prototypical drugs as the choline motif, the tropane motif, and the benzylidene motif. The choline motif involves the location of an oxygen-containing polar group such as a hydroxyl or carbonyl separated by two carbons from the charged nitrogen. The tropane motif provides ␣7-selectivity based on the addition of multiple small hydrophobic groups positioned away from the cationic center in specific orientations. We show that this motif can convert the nonselective agonists quinuclidine and ethyltrimethyl-ammonium to the ␣7-selective analogs methyl-quinuclidine and diethyldimethyl-ammonium, respectively. We have shown previously that the benzylidene group of 3-2,4, dimethoxy-benzylidene anabaseine (GTS-21) converts anabaseine into an ␣7-selective agonist. The benzylidene motif was also applied to quinuclidine to generate another distinct family of ␣7-selective agonists. Our results provide insight for the further development of nicotinic therapeutics and will be useful to direct future experiments with protein structure-based modeling and site-directed mutagenesis.The nicotinic acetylcholine receptors of the brain can be broadly divided into two classes: heteromeric ␤-subunit-containing receptors, and homomeric ␣7-type receptors. Homomeric ␣7-type receptors have emerged as an exciting potential therapeutic target for several indications, and this has encouraged the development of ␣7-selective agonists. This path of drug development relies on the consideration of both features that distinguish the heteromeric receptors from the homomeric receptors and features that distinguish selective agonists from nonselective agonists.Both heteromeric, ␤-subunit-containing receptors and homomeric ␣7-type receptors are pentameric. The heteromeric neuronal nAChR contain at least one or more ␣ subunits (␣2-␣6) and additional ␤ subunits (␤2-␤4), with two agonist binding sites located at the interface between ␣ and ␤ subunits (Dani, 2001). Neuronal nicotinic receptor ␣ subunits are classified as such based on sequence homology to the ␣ subunits of muscle-type receptors (Heinemann et al., 1990), and essential conserved aspects of muscle and neuronal ␣ subunits provide specialized subdomains that contribute to the primary face of an asymmetrical binding site for acetylcholine and other agonists. In contrast, there is structural homology b...

Activation and Desensitization of Nicotinic α7-type Acetylcholine Receptors by Benzylidene Anabaseines and Nicotine

“…It was proposed that the large hydrophobic groups present on ␣7-selective agonists such as the BA compounds are accommodated within a comparably large hydrophobic pocket in the ␣7 agonist binding site (Horenstein et al, 2008). This would be consistent with the hypothesis that these agonists may remain bound to the receptor even after being washed out of the bath.…”

“…Many experimental agents have been identified that selectively activate ␣7 nAChR (Horenstein et al, 2008). The structural diversity of these agents is matched by a diversity in their functional properties, for example, in regard to whether they act as antagonists of other nAChR subtypes and/or 5-hydroxytryptamine 3 (5HT 3 ) receptors.…”

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

“…Both academic and industrial laboratories have discovered numerous agonists with selectivity for ␣7 receptors (Horenstein et al, 2008), and in recent years an alternative therapeutic approach based on allosteric modulation has gained momentum because of the discovery of many structurally diverse positive allosteric modulators (PAMs) that are selective for ␣7 receptors (Williams et al, 2011c). To date, the ␣7 PAMs are classified into one of two categories based on their properties of modulation.…”

Synthesis of Selective Agonists for the α7 Nicotinic Acetylcholine Receptor with In Situ Click-Chemistry on Acetylcholine-Binding Protein Templates

“…The most potent and selective compound, triazole 22 q , features a positively charged N-methylammonium tropane and aromatic methyleneoxynaphthylenethanone. The other products formed revealed pharmacophore models for leads that were consistent with studies on ␣7 nAChRs (Horenstein et al, 2008), which demonstrated the recognition capacity of the template to select preferred binding partners. Structural Insights into ␣7 nAChR Selectivity from AChBP Data.…”