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(19) United States (12) Patent Application Publication (10) Pub US 20070049576A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0049576 A1 Barlow et al. (43) Pub. Date: Mar. 1, 2007 (54) NEUROGENESIS BY MUSCARINIC Related US. Application Data RECEPTOR MODULATION (60) Provisional application No. 60/711,846, ?led on Aug. 26, 2005. Provisional application No. 60/727,127, (75) Inventors: Carrolee Barlow’ Del Mar’ CA (Us); ?led on Oct. 14, 2005. Provisional application No. Tood A_ Carter San Diego CA (Us). 60/738,133, ?led on Nov. 17, 2005. Provisional appli Kym L Lorrain’ San Diego’ CA (USS, cation No. 60/803,826, ?led on Jun. 2, 2006. Jammieson C. Pires, San Diego, CA P bl' t' Cl '? t' (US); Andrew Morse, San Diego, CA u lea Ion assl ca Ion (US); Dana Gitnick, San Marcos, CA (51) Int CL (US); Kai Treuner, San Diego, CA A61]; 31/55 (200601) (US); Alex Broadhead, San Diego, CA A61K 31/473 (200701) (US) A61K 31/4745 (2007.01) A61K 31/445 (2006.01) A61K 31/403 (2007.01) Correspondence Address: A61K 31/66 (2006.01) TOWNSEND AND TOWNSEND AND CREW, (52) US. Cl. .................. .. 514/214.03; 514/295; 514/297; LLP 514/319; 514/411; 514/114 TWO EMBARCADERO CENTER EIGHTH FLOOR (57) ABSTRACT SAN FRANCISCO, C A 941114.834 (Us) The instant disclosure describes methods for treating dis eases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The dis (73) Assignee; Braincells, Inc,’ San Diego, CA closure includes compositions and methods based on mus carinic receptor modulation, such as via inhibition of ace (21) Appl, No.1 11/467,527 tylcholine esterase (AChE) activity, alone or in combination With another neurogenic agent to stimulate or activate the (22) Filed: Aug. 25, 2006 formation of neW nerve cells. Patent Application Publication Mar. 1, 2007 Sheet 1 0f 15 S m A 1 WwEEEouQmmgimom3:55Ecosmz I5. 0:00As:molU w$0M3:9:32w #6mum is ,7“ 0.x.:5.m?.c6.m6.m.m.Qm-mzm-o6.m6. 259mP 3:232EEEEQEQE?b OFIII w>=_won_6:2826:50. mEEEooQmwI I I O Q é o: IOJIIUOQ amused JO iuamad Patent Application Publication Mar. 1, 2007 Sheet 2 0f 15 US 2007/0049576 A1 mEEEouamm wSmEN m..m.9.?m“?m...~.m.”o.m6.Q“-c6-Qm- 850:2SEEEQEQEEQ E3503.. OM@5252‘an“Snows wEEEoonmwI q.H.m 5E ..o .éov ‘om ‘cw ‘on low lam low ‘on ‘cm .2. oT |onuog aAmsod 4o IIUGOJGd Patent Application Publication Mar. 1, 2007 Sheet 3 0f 15 US 2007/0049576 A1 Figure3 CellCount -a.o-7.5-7.o-6.5-6.0-5.5-5.o4.54.0-3.5 LogConc(M) Sabcomeline-I- |onuog amused 4o waxed Patent Application Publication Mar. 1, 2007 Sheet 4 0f 15 US 2007/0049576 A1 _>__:wgmeo?mwlf265083.!2.65833212218 wSmEw 550.5:mEsI2.50mEEEoonmwn>mmm< Z8Z3230350NZS$28 A2335; #Fzo@581nxlmémmmzil.Ezo oom omv. 00.‘ 0mm oom omm ooN cm? 09. Patent Application Publication Mar. 1, 2007 Sheet 5 0f 15 US 2007/0049576 A1 Patent Application Publication S 6 5 US 2007/0049576 Al n,no.0258 .<2QE¢>|¢| M a669:9:II:000? w08 moow 0m09¢ m3m?owmmon 9:5@ B6883“526,12:94mEwoQ 8.61we;25 QONF- , com 0 (LUO) p9|8A8Ji eouelsgq Patent Application Publication Mar. 1, 2007 Sheet 7 0f 15 US 2007/0049576 A1 @SmEN 2EE6256¢ com com on? so? Patent Application Publication w 2 0 S 2 0 % 7 6 A 1 M25055555.5955.6 M8 Mo Mow Um mSmEw 1,8 88 820mE_>>wuwwkw5o<mEwoQ wm u0 EBe fB WSmm hn mv 2 S W Patent Application Publication Mar. 1, 2007 Sheet 9 0f 15 US 2007/0049576 A1 oEoEO wSmEa umwww?asw>:w>ozmEummm “mum;rod oov ooN cm? 00? cm (spuooas) 123 o; Aouaun (s) 1,23 o1/ioue1e1 Patent Application Publication Mar. 1, 2007 Sheet 10 0f 15 US 2007/0049576 A1 mod wSmEF oczwEoonmm 3:232“_o>ozL83:23“0030 v0.0 EQEEQF8x55 22%; (%) GOUGJGJGJCI ueew Patent Application Publication Mar. 1, 2007 Sheet 11 0f 15 US 2007/0049576 A1 925P 202% LUUJ ogqng Jed s||eQ eAmsod np19 ueew Patent Application Publication Mar. 1, 2007 Sheet 12 0f 15 US 2007/0049576 A1 23mm8 o\o$00o_oEm>.w> >>wz2252 33E6.0%? it,355mo. Patent Application Publication Mar. 1, 2007 Sheet 13 0f 15 US 2007/0049576 A1 Figure 13 Novelty Suppressed Feeding 25:23omwvmmAmC mmmMw0 0_ * m. V w k Fluoxetine 5.0 Sabcomeline 0.01 Combination BrdU Posi ive Cells in Granule Cell Layer I Vehicle 10000 I] Fluoxetine Q Sabcomel me Comb ination eQwowoooooovooooo4 000000v 090 000000o m. rOv 000000066606660660696.i0 06000946.406A 0_ 6606.00>O0O A a@ 0 0. * p987654321 000000000< 000000000 Dorsal Hippocampus Ventral Hippocampus000000o“onooo0%oo00000000000000.0000.000000000 00000000000 5 oooonororonouonovovovorovovenowowowoooooooné 000.0000‘00000000000000?00000.oooooooooooooooooz Patent Application Publication Mar. 1, 2007 Sheet 14 0f 15 US 2007/0049576 A1 - Figure 14 Captopril _Donepezil AVG Neuronal Differentiation (T UJ1) 15o: -I-Captopri| _Donepezi| i 140' "0- Captopril - 120- .W' Donepezil '. PercentofPositiveControl N O -8.5 1o'-8.0 10'-7.5 10I-7.0 10.-6.5 1 o'-6.0 1 0.6.5 1 0'-5.0 10.4.5 10.4.0 Conc (M) Patent Application Publication Mar. 1, 2007 Sheet 15 0f 15 US 2007/0049576 A1 Figure 15 Buspirone + Donepezil Astrocyte Differentiation (GFAP) 110' -I-Buspirone_Donepezi| 100' --A- Buspirone 90 80 70' 60 PercentofPositiveControl 50- I‘ -8.5 10'-8.0 10'-7.5 1o'-7.0 10.6.5 1o'-6.0 10'-5.5 1o'-5.0 10.4.5 10.4.0 Conc (M) US 2007/0049576 A1 Mar. 1, 2007 NEUROGENESIS BY MUSCARINIC RECEPTOR m1 receptors are found in the CNS and peripheral ganglia, MODULATION m2 receptors are found on cardiac cells and in the brainstem, m3 receptors are found in smooth muscle, endocrine (e.g., CROSS-REFERENCES TO RELATED the pancreas) and exocrine glands (e. g., the lacrimal glands), APPLICATIONS and the cerebral cortex, m4 receptors are found primarily in [0001] This application claims bene?t of priority under 35 the neostriatum, and m5 receptors are found primarily in the USC § 119(e) from US. Provisional Patent Applications substantia nigra. Muscarinic receptors are G-protein coupled 60/711,846, ?led Aug. 26, 2005; 60/727,127, ?led Oct. 14, receptors (GPCRs), With the activity of the m1, m3 and m5 2005; 60/738,133, ?led Nov. 17,2005; and 60/803,826, ?led receptors mediated by the phosphoinositide second-messen Jun. 2, 2006; all four of Which are hereby incorporated by ger system, and the m2 and m4 receptors linked to the reference as if fully set forth. adenylate cyclase second messenger system. [0006] Compounds With activity against muscarinic recep FIELD OF THE DISCLOSURE tors have been studied for the treatment of conditions linked [0002] The instant disclosure relates to methods for treat to cholinergic dysfunction, such as AlZheimer’s Disease, ing diseases and conditions of the central and peripheral Which is associated With the degeneration of cholinergic nervous system by stimulating or increasing neurogenesis neurons in the forebrain. Clinical testing has revealed a high via modulation of muscarinic receptor activity, including via degree of debilitating, dose-limiting side effects associated inhibition of acetylcholine esterase (AChE) activity in com With compounds active against the m2 and m3 receptor bination With another neurogenic agent. The disclosure subtypes, including cardiovascular and gastrointestinal side includes methods based on the application of a neurogenesis effects. In contrast, compounds that are selective for m1 modulating agent having activity against muscarinic recep receptors, or m1 and m4 receptors have generally been tors and/ or an AChE inhibitor With another neurogenic agent found to have better clinical pro?les, With enhanced e?icacy to stimulate or activate the formation of neW nerve cells. and decreased side effects. To date, there is has been little research regarding the use of muscarinic compounds to treat BACKGROUND OF THE DISCLOSURE diseases not characteriZed by or substantially resulting from [0003] Neurogenesis is a vital process in the brains of cholinergic dysfunction. animals and humans, Whereby neW nerve cells are continu [0007] Acetylcholinesterase, or AChE, is also knoWn as ously generated throughout the life span of the organism. erythrocyte (or RBC) cholinesterase and acetylcholine The neWly born cells are able to differentiate into functional acetylhydrolase. It is classi?ed at EC 3.1.1.7 and is found in cells of the central nervous system and integrate into exist various locations, including the blood and neural synapses. ing neural circuits in the brain. Neurogenesis is knoWn to AChE catalyZes hydrolysis of the neurotransmitter acetyl persist throughout adulthood in tWo regions of the mamma choline into choline and acetic acid Where acetylcholine is a lian brain: the subventricular Zone (SVZ) of the lateral pan-muscarinic and pan-nicotinic receptor ligand. The ventricles and the dentate gyrus of the hippocampus. In these hydrolysis reaction reaction permits an activated cholinergic regions, multipotent neural progenitor cells (NPCs) continue neuron to return to a resting state. to divide and give rise to neW functional neurons and glial cells (for revieW Gage 2000). It has been shoWn that a [0008] Citation of the above documents is not intended as variety of factors can stimulate adult hippocampal neuro an admission that any of the foregoing is pertinent prior art. genesis, e.g., adrenalectomy, voluntary exercise, enriched All statements as to the date or representation as to the environment, hippocampus dependent learning and anti contents of these documents is based on the information depressants (Yehuda 1989, van Praag 1999, BroWn J 2003, available to the applicant and does not constitute any admis Gould 1999, Malberg 2000, Santarelli 2003).
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