Synthesis and evaluation of N 1 -alkylindole-3-ylalkylammonium compounds as nicotinic acetylcholine receptor ligands Edwin G. Pérez a,c,⇑ , Bruce K. Cassels b,c , Christoph Eibl d,  , Daniela Gündisch d,  a Facultad de Química, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Casilla 306, Correo 22, Santiago, Chile b Department of Chemistry, Faculty of Sciences, University of Chile, Casilla 653, Santiago, Chile c Millennium Institute for Cell Dynamics and Biotechnology, Plaza Ercilla 847, Santiago, Chile d Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany article info Article history: Received 12 April 2011 Revised 17 April 2012 Accepted 25 April 2012 Available online 2 May 2012 Keywords: Nicotinic acetylcholine receptors Affinity Indolylalkylamines Structure–activity relationships abstract In this study thirty-three novel indole derivatives were designed and synthesized based on the structure of deformylflustrabromine B (1), a metabolite isolated from the marine bryozoan Flustra foliacea L. The syntheses were carried out using standard methodologies and in good yields. The molecules were tested for their affinities for the a4b2 / , a3b4 / , a7 / and (a1) 2 b1cd nicotinic acetylcholine receptor (nAChR) sub- types. Binding assays showed that, among these ligands, compound 7c exhibited the highest affinity with K i = 136.1, 93.9 and 862.4 nM for the a4b2 / , a3b4 / , and a7 / nAChRs subtypes, respectively. These results indicated that the indole core might be a useful scaffold for the development of new potent and selective nAChR ligands. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Nicotinic acetylcholine receptors (nAChR) are prototypical li- gand-gated ion channels that mediate fast synaptic transmission. 1 These receptors are pentameric proteins comprising either five copies of the same (or different) a subunit(s) or combinations of two different types of subunits (a and b) in the neuronal subtypes, or two a1, one b1, one c and one d (or e) subunit in the neuromus- cular subtype, symmetrically arranged around a central ion pore. 2 Nine different types of a subunits (a2–a10) and three kinds of b subunits (b2–b4) have been cloned and characterized as constitu- ents of neuronal nAChR. The physiological ligand of nAChR is acetylcholine (ACh); however, tobacco components such as nico- tine (Nic) and [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] (NNK) are known to be high-affinity agonists of nAChR, and nico- tine is the primary addictive component of tobacco smoke. 3–5 Binding of ligands such as ACh, Nic or NNK induces a conforma- tional change in the receptor that opens the ion channel to transmit signals at neuromuscular junctions and synapses in the central and peripheral nervous systems. 2 Charged amino acids line the channel pore and select the ions that pass through the channel. 3 Natural compounds acting on the central nervous system have played an important role in drug discovery and are the source of numerous therapeutic agents, 6 and the cholinergic system is a target frequently mentioned in the literature. 7–9 Among them, bungarotoxins, conotoxins, methyllycaconitine, anatoxin-a and epibatidine have often been discussed as molecular probes for the receptor but rarely as potential drugs because of their toxicity and/or low selectivity, while nicotine and cytisine have been used to facilitate smoking cessation in various formulations (e.g., tablets, gum, spray, patches and herbal preparations). Finally, varenicline, inspired in the structure of cytisine, was launched on the market in 2006 and is commercialized as a smoking cessation agent. 10 Although marine natural products appear frequently in the lit- erature as potent agents acting on the CNS, they have usually been overlooked and have only recently arisen as possibly valuable drug leads. Among them, those with an indole moiety represent a rich group with tremendous potential for the design and development of drugs for the treatment of various psychiatric diseases and disorders. 11,12 Tryptamine [2-(1H-indol-3-yl)ethanamine] derivatives deform- ylflustrabromine B (1) and deformylflustrabromine (2), isolated from the widespread marine bryozoan Flustra foliacea L., showed weak binding affinities at a7 and a4b2 nAChRs, respectively, 13 and deformylflustrabromine (2) was identified as a positive allo- steric modulator (PAM) of a4b2 nAChR. 14,15 Quite recently it was shown that compound 2 not only potentiates the responses to both partial and full agonists but has no effect when it is co-applied with antagonists. 16 Deformylflustrabromine B (1) did not increase 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.04.050 ⇑ Corresponding author. E-mail address: eperezh@uc.cl (E.G. Pérez).   Present address: Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA. Bioorganic & Medicinal Chemistry 20 (2012) 3719–3727 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc