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(12) Patent Application Publication (10) Pub. No.: US 2005/0033522 A1 Wainer Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0033522 A1 Wainer Et Al US 20050033522A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0033522 A1 Wainer et al. (43) Pub. Date: Feb. 10, 2005 (54) COMPUTER-BASED MODEL FOR Related U.S. Application Data IDENTIFICATION AND CHARACTERIZATION OF (63) Continuation-in-part of application No. 10/411,206, NON-COMPETITIVE INHIBITORS OF filed on Apr. 11, 2003. NCOTINIC ACETYLCHOLINE RECEPTORS AND RELATED LIGAND-GATED ON Publication Classification CHANNEL RECEPTORS (51) Int. Cl." .......................... G06F 19/00; G01N 33/48; (76) Inventors: Irving W. Wainer, Washington, DC GO1N 33/50 (US); Krzysztof Jozwiak, Abingdon, (52) U.S. Cl. ................................................................ 702/19 MD (US); Ruin Moaddel, Germantown, MD (US); Sarangan (57) ABSTRACT Ravichandran, Frederick, MD (US); A computer readable medium holding data of a molecular Jack R. Collins, Frederick, MD (US) model of a ligand-gated ion channel receptor and/or a computer System for modeling Said receptor are provided by Correspondence Address: the instant invention. The molecular model can be used to BRCH STEWART KOLASCH & BRCH design novel compounds having activity as non-competitive PO BOX 747 inhibitors of the ion channel. A preferred embodiment of the FALLS CHURCH, VA 22040-0747 (US) invention relates to nicotinic acetylcholine receptorS. Com pounds having activity as non-competitive inhibitors of (21) Appl. No.: 10/820,809 ligand-gated ion channel receptors and methods for inhib iting the receptor and treating diseases or disorderS mediated (22) Filed: Apr. 9, 2004 by function of the receptor are also disclosed. Patent Application Publication Feb. 10, 2005 Sheet 1 of 16 US 2005/0033522 A1 ONE SUBUNT OF nAChR - N NH2 UGAND-BINDING STE Soffee CROSS-SECTION OF FME ASSEMBLED SUBUNITS (2xa + 3x p) OF nAChR i: T. IONSGolf PASS CYTOPLASMIC Epo FOUR HYDROPHOBC S 5 4. TRANSMEMBRANE . BINDING STE FOR DOMAINS (M1-M4) NEUROTRANSMITTER 5 B SUBUNIT O SUBUNIT 7 ACELULAR u? CYTOPLASMIC CHANGE IN INTRACEULAR ON CONCENTRATION FIG.1 Patent Application Publication Feb. 10, 2005 Sheet 2 of 16 US 2005/0033522 A1 (Z–)ONIJONSYldOIX0 ?J?GYIMISV0W|}}}}}/W» (91)ONIHENOTEIl (II)ONIHENOBI (8)ONIHENIMES (*)ONIHEN|NOBAHI „(ZZ)ONIHMINTEOVNIXG|—À (GI)ONIHENTWA|<--> (1)ONIHTIMEWARINI\<---> Patent Application Publication Feb. 10, 2005 Sheet 3 of 16 US 2005/0033522 A1 FIG.3a Patent Application Publication Feb. 10, 2005 Sheet 4 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 5 of 16 US 2005/0033522 A1 3 3 s S Patent Application Publication Feb. 10, 2005 Sheet 6 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 7 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 9 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 10 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 11 of 16 US 2005/0033522 A1 Patent Application Publication Feb. 10, 2005 Sheet 12 of 16 US 2005/0033522 A1 - DEXTROMETHORPHAN - LEVOMETHORPHAN O 20 40 60 80 100 RETENTION TIME (min) FIG.11 Patent Application Publication Feb. 10, 2005 Sheet 13 of 16 US 2005/0033522 A1 FIG.12b Patent Application Publication Feb. 10, 2005 Sheet 14 of 16 US 2005/0033522 A1 2.4 - S / 2.2 | CLOZAPINE 20 | 1.8 / y : LOGK VERAPAML VERAPAML 1.6 | Q Q EuroPh. 8 DLTHAZEN": S 1.4 p LEVOETHORPHAN METHADONE 9 ETRORPHAN 1.2 w \::i- " :: us;5People.1,953OMF: O 5-1 QMK-801 N. -76 A MENANTINE \ -8.0 ECAMANNEó oBUPROPON -8,4- Eurt. EHONO -88 N. f gouro Patent Application Publication Feb. 10, 2005 Sheet 15 of 16 US 2005/0033522 A1 FIG.14 Patent Application Publication Feb. 10, 2005 Sheet 16 of 16 US 2005/0033522 A1 250000 200000 150000 100000 50000 LOGNC FIG.15 US 2005/0033522 A1 Feb. 10, 2005 COMPUTER-BASED MODEL FOR Torpedo marmorata has been examined by Unwin and IDENTIFICATION AND CHARACTERIZATION OF coworkers using cryo-electron microscopy and revealed the NON-COMPETITIVE INHIBITORS OF NCOTINC conical shape of the channel portion of the receptor and the ACETYLCHOLINE RECEPTORS AND RELATED relationship of the membrane-Spanning helices to each other LGAND-GATED ON CHANNEL RECEPTORS (see FIG. 1). In spite of these unprecedented advances in 0001. The present application is a Continuation-In-Part resolving the Structures of transmembrane proteins, the of U.S. application Ser. No. 10/411,206, filed Apr. 11, 2003, detailed, atomic resolution, Structure of the entire nAChR the entire contents of which are hereby incorporated by family remains unresolved. reference and for which priority is claimed under 35 U.S.C. 0007 Muscular nAChRs are located at the nerve-muscle S 120. junctions and are responsible for triggering motor motion, 0002 The present application includes an appended and neuronal nAChRs, widely distributed in the nervous Sequence Listing of 15 amino acid Sequences and Appen System, are involved in the fast Synaptic transmission of dices 1 to 5 providing computer programming Scripts, inter-neuronal communication. It is known that these recep parameter files and atomic coordinates of computer models tors are structurally similar in their overall composition but of the luminal channel portion of the ligand-gated ion differ in the exact make-up of the protein Subunits forming channel Subtypes. the receptorS. 0008 The nicotinic acetylcholine receptor (nAChR) is FIELD OF THE INVENTION presently the best characterized member of the ligand-gated ion channel Superfamily. The nicotinic receptors are of great 0003. The present invention relates to a computer system therapeutic importance. The Subunits assemble combinato for generating molecular models of ligand-gated ion chan rily to form a variety of pentameric transmembrane protein nels and in particular, molecular models of the inner lumen Subtypes. of a ligand-gated ion channel and associated binding pock ets. The present invention further relates to a computer 0009. Each receptor is formed by bringing together five System Simulating interaction of the computer-based model Separate trans-membrane proteins, each containing a large of the ligand-gated channel and non-competitive inhibitor extra-cellular N-terminal domain, four membrane Spanning compounds for identification and characterization of non alpha helices (M1, M2, M3, and M4) and a small C-terminal competitive inhibitors and to inhibitor compounds So dis domain (see FIG. 1). Two, homologous, neurotransmitter covered. The present invention also relates to methods for binding sites are formed by the N-terminal domains where treating various disorders related to ligand-gated ion channel cholinergic agonist and competitive antagonists bind, and receptor function. The invention also provides a way to are the usual targets for drug design. The ion channel is examine compounds for “off-target activity that may cause formed by a pentameric arrangement of the M2 helical undesirable side effects to a desired target activity or that segments contributed by the five proteins (see FIG. 2). The may represent a new therapeutic activity for a known channel Specificity, characteristic of each receptor Subtype, compound. is controlled by the identity of each of the M2 helices. 0010 Neuronal nicotinic acetylcholine receptors BACKGROUND OF THE INVENTION (nAChRs) are the class of ligand-gated ion channels of the 0004 Ligand gated ion channels (LGICs) are currently central and peripheral nervous System that regulate Synaptic very important targets for drug discovery in the pharmaceu activity. The basic structure of the nAChR is shown in tical industry. The Superfamily is separated into the nicotinic FIGS. 1 and 2. Referring to FIG. 1, nAChR consists of five receptor Superfamily (muscular and neuronal nicotinic, transmembrane Subunits 1, 2, 3, 4, 5 oriented around a GABA-A and -C, glycine and 5-HT3 receptors), the exci central pore 6 permeable to cations. Cations flow through the tatory amino acid Superfamily (glutamate, aspartate and pore is regulated by ligand binding. The Subunits in nAChR kainate receptors) and the ATP purinergic ligand gated ion are typically C. Subunits and B Subunits. channels. These families only differ in the number of trans 0011. At present, 12 different homologous subunits have membrane domains found in each Subunit (nicotinic-4 been identified in neuronal nAChRs, 9 C. Subunits (C2-C-10) transmembrane domains, excitatory amino acid recep and 3 B subunits (B2-34). The major difference between C. tors-3 transmembrane domains, ATP purinergic LGICs-2 and B Subunits is the presence and location of the disulfide transmembrane domains). bond formed by two adjacent cysteines in the C. Systems, the 0005 Nicotinic acetylcholine receptors (nAChRs) are a absence of this feature distinguishes non-C. Subunits. This family of ligand gated ion channels that control the fast disulfide bond located on the extracellular domain plays an permeation of cations through the postsynaptic cell mem important role in neurotransmitter binding as well as the brane when stimulated by acetylcholine. Physiologically, mechanism of channel opening. These Subunits combine to nAChRS are key targets in drug discovery for a number of form multiple nAChR Subtypes and predominant Stoichiom diseases, including Alzheimer's and Parkinson's disease, etry is (C)(B), however pentamers containing only C. and have been widely discussed and investigated. Subunit are also known e.g., (C7). In case of muscular nAChR the Stoichiometry is more complicated, the muscular 0006 Structural and functional studies of nAChRs have led to the elucidation of three physiological States of the nAChR receptor is predominantly described as (C)(3öy. receptor: 1) resting (channel closed); 2) acetylcholine stimu 0012. The nAChRs are very complex systems with doz lated (channel open); and 3) a desensitized State where the ens of potential different binding domains for different ion flux is inhibited even in the presence of neurotransmitter. classes of compounds of both endo- and exogenous origin The overall Structure of nicotinic acetylcholine receptor of (Arias H.
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