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Therapeutic Potential of A7 Nicotinic Acetylcholine Receptors

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Therapeutic Potential of A7 Nicotinic Acetylcholine Receptors 1521-0081/67/4/1025–1073$25.00 http://dx.doi.org/10.1124/pr.113.008581 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:1025–1073, October 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: TIMOTHY A. ESBENSHADE Therapeutic Potential of a7 Nicotinic Acetylcholine Receptors Daniel Bertrand, Chih-Hung L. Lee, Dorothy Flood, Fabrice Marger, and Diana Donnelly-Roberts HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.) Abstract. ...................................................................................1025 I. Introduction. .............................................................................1026 II. From Gene to Function .....................................................................1028 A. The CHRNA7 Gene and Its Variants....................................................1028 Downloaded from B. Functional Properties of a7 Nicotinic Acetylcholine Receptors . ........................1030 C. The a7 Nicotinic Acetylcholine Receptor as a Prototypical Allosteric Protein . ............1034 D. The a7 Nicotinic Acetylcholine Receptor Heteromers ....................................1035 E. Effects of Chronic Exposure of a7 Nicotinic Acetylcholine Receptors . ..................1036 F. Modulation of a7 Nicotinic Acetylcholine Receptor Signaling.............................1037 pharmrev.aspetjournals.org G. Expression and Function of a7 Nicotinic Acetylcholine Receptors in Brain . ............1038 III. Ligands Active at a7 Nicotinic Acetylcholine Receptors. ....................................1039 A. Structure-Activity Relationship of a7 Nicotinic Acetylcholine Receptor Agonists ..........1039 1. The Clinical Trials.. .................................................................1042 B. From the Crystal Structure to Developments in Structure-Activity Relationship . ......1043 C. Target Engagement and Overview of the Development of Biomarkers. ..................1044 D. The Chemical Strategy for a7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators .............................................................................1044 at Universite Laval on October 1, 2015 IV. The Relevance of a7 Nicotinic Acetylcholine Receptors in Diseases . ........................1047 A. Alzheimer’s Disease . .................................................................1047 B. Schizophrenia . .......................................................................1050 C. Autism .................................................................................1052 D. Microdeletion Syndrome ................................................................1053 E. Parkinson’s Disease . .................................................................1054 F. Nonneuronal Related Diseases..........................................................1056 1. Cancer. .............................................................................1056 G. a7 Nicotinic Acetylcholine Receptors and the Immune Connection .......................1057 1. Sepsis. .............................................................................1058 2. Inflammatory Bowel Disease, Focus on Ulcerative Colitis. ............................1058 3. a7 Nicotinic Acetylcholine Receptors and Osteoarthritis. .............................1059 H. a7 Nicotinic Acetylcholine Receptors and Cardiac Function ..............................1060 I. The Role of a7 Nicotinic Acetylcholine Receptors in Renal Function......................1060 V. Conclusions . .............................................................................1062 Acknowledgments . .......................................................................1063 References .................................................................................1063 Abstract——Progress in the fields of neuroscience and nicotinic acetylcholine receptors (nAChRs) has high- molecular biology has identified the forebrain choliner- lighted, in particular, the role of a7nAChRsinthese gic system as being important in many higher order brain higher order brain functions as evidenced by their functions. Further analysis of the genes encoding the peculiar physiologic and pharmacological properties. As Address correspondence to: Daniel Bertrand, HiQScreen Sàrl, 6, rte de Compois, 1222 Vésenaz, Geneva, Switzerland. E-mail: daniel. [email protected] dx.doi.org/10.1124/pr.113.008581. 1025 1026 Bertrand et al. this receptor has gained the attention of scientists from affecting a7 nAChRs into therapeutics has to date only academia and industry, our knowledge of its roles in progressed to the stage of testing in clinical trials. various brain and bodily functions has increased im- Notably, however, most recent human genetic and bio- mensely. We have also seen the development of small chemical studies are further underscoring the crucial molecules that have further refined our understanding of role of a7 nAChRs and associated genes in multiple organ the roles of a7 nAChRs, and these molecules have begun systems and disease states. The aim of this review is to to be tested in clinical trials for several indications. discuss our current knowledge of a7 nAChRs and their Although a large body of data has confirmed a role of a7 relevance as a target in specific functional systems and nAChRs in cognition, the translation of small molecules disease states. I. Introduction 1988; Gopalakrishnan et al., 1995). Several genes encoding for nAChRs were identified from different invertebrate Although nicotine is the most widely used “recrea- and vertebrate species. Genes encoding for the neuronal tional drug” for more than 400 years, our understanding nAChRs were identified and subsequently classified as of its effects on the brain remains limited. With the CHRNA and CHRNB (CHRNA2–10 and CHNRB2–4)and introduction in 1929 of electroencephalography, nicotine their chromosomal localizations were identified in the exposure was found to cause modifications of brain human genome, as illustrated by the human karyotype electrical activity but provided no insights into the – – possible mechanisms underlying these modifications shown in Fig. 1A. CHRNA2 10, encoding the a2 10 (reviewed in Yamamoto and Domino, 1965). In the first subunits of neuronal nAChRs, were defined as sharing intracellular recordings conducted in brain slices, nico- homology with the gene encoding for the a1nAChR tine exposure failed to demonstrate significant activity; subunit of the neuromuscular junction and, more specifi- thus it was concluded that nicotine did not mimic the cally, in the extracellular domain with the presence of two – agonist acetylcholine (ACh). Histologic investigations adjacent cysteines corresponding to amino acids 192 193 carried out at approximately the same time revealed, in the Torpedo marmorata sequence, from which the a1 however, surprising results illustrating that the toxin nAChR subunit was cloned (Devillers-Thiery et al., 1979). from the snake Bungarus multicintus (a-bungarotoxin, In the case of the adult form of the neuromuscular junction a-Btx), which displays a high affinity for muscle nAChRs, nAChR, ACh binds at the interface between a and d or a abundantly labeled specific regions in brain slices and and « subunits (Pedersen and Cohen, 1990; Changeux and that this labeling was displaced by incubation with Edelstein, 1994; Karlin and Akabas, 1995). Subsequently, nicotine (Clarke et al., 1985). Two possibilities could genes encoding for neuronal nAChRs were isolated simul- explain the discrepancy between electrophysiological taneously in avians (chick) and in the rat and were initially and histologic studies, either a nonspecific binding of divided into a and b subunits according to the presence of a-Btx with no functional significance occurred or the two adjacent cysteines equivalent to those observed in the absence of a functional signal detected by intracellular a1 subunit of the muscle receptors. Functional receptors recording resulted in a false negative finding. were observed only with coexpression of a and b subunits, Cloning of the neuromuscular junction nAChRs marked suggesting that the a subunit harbors the principal a turning point for the investigation of ligand-gated ion component for the ACh binding site, whereas the b subunit channels and offered the possibilities for investigation of wasconsideredasaconstitutive subunit. However, since related proteins at the proteomic and genomic levels. In these initial studies, it has been shown that both the a and addition, the availability of complementary DNA and the b subunits contribute to the formation of the ligand- mRNA allowed reconstitution of functional proteins in binding domain (LBD) in the neuronal nAChRs in which host systems such as Xenopus laevis oocytes or cell lines ACh binds at the interface between an a and an adjacent (Miledi et al., 1982; Barnard et al., 1982; Ballivet et al., subunit. ABBREVIATIONS: ACh, acetylcholine; AChBP, acetylcholine binding protein; AKI, acute kidney injury; AD, Alzheimer’s disease; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; APP, amyloid precursor protein; ASD, autism spectrum disorder; Ab, amyloid-b; BACE1, b-site amyloid precursor protein-cleaving enzyme 1; BD, bipolar disorder; bp, base pair; BP, break point; a-Btx, a-bungarotoxin; [11C]CHIBA-1001, 1,4-diazabicyclo-[3.2.2]nonane analog 4-[11C]methylphenyl 2,5-diazabicyclo[3.2.2]noane-2- carbocylate; CD,
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