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(12) Patent Application Publication (10) Pub. No.: US 2010/0120842 A1 Barlow Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0120842 A1 Barlow Et Al US 20100120842A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0120842 A1 Barlow et al. (43) Pub. Date: May 13, 2010 (54) NEUROGENESIS BY MUSCARINIC Related U.S. Application Data RECEPTORMODULATION (62) Division of application No. 1 1/467,527, filed on Aug. (75) Inventors: Carrolee Barlow, Del Mar, CA 25, 2006, now Pat. No. 7,678,363. (US); Todd A. Carter, San Diego, (60) Provisional application No. 60/711,846, filed on Aug. CA (US); Kym I. Lorrain, San 26, 2005, provisional application No. 60/727,127, Diego, CA (US); Jammieson C. filed on Oct. 14, 2005, provisional application No. Pires, San Diego, CA (US); 60/738,133, filed on Nov. 17, 2005, provisional appli Andrew Morse, San Diego, CA cation No. 60/803,826, filed on Jun. 2, 2006. (US); Dana Gitnick, San Marcos, CA (US); Kai Treuner, San Diego, Publication Classification CA (US); Alex Broadhead, San (51) Int. Cl. Diego, CA (US) A63L/439 (2006.01) A6IP 25/22 (2006.01) Correspondence Address: A6IP 25/18 (2006.01) SUGHRUE MION, PLLC (52) U.S. Cl. ........................................................ S14/305 2100 PENNSYLVANIA AVENUE, N.W., SUITE 8OO (57) ABSTRACT WASHINGTON, DC 20037 (US) The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system (73) Assignee: BrainCells, Inc., San Diego, CA by stimulating or increasing neurogenesis. The disclosure (US) includes compositions and methods based on muscarinic receptor modulation, Such as via inhibition of acetylcholine (21) Appl. No.: 12/692,365 esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the forma (22) Filed: Jan. 22, 2010 tion of new nerve cells. Neuronal Differentiation (TUJ1) SabComeline O Positive Neuronal Control -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 -3.5 Log Conc (M) SabCorneline Positive Neuronal Control Neuronal ECs 8.04 5.28 (ul) Patent Application Publication May 13, 2010 Sheet 1 of 15 US 2010/O120842 A1 Figure 1 Neuronal Differentiation (TUJ1) SabCOmeline 1 OO O Positive Neuronal Control -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 -3.5 Log Conc (M) Sabconneline Positive Neuronal Control Neuronal EC so 8.04 5.28 Patent Application Publication May 13, 2010 Sheet 2 of 15 US 2010/O120842 A1 Figure 2 Astrocyte Differentiation (GFAP) 100 90 SabCOmeline -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 -3.5 Log Conc (M) Sabconneline Astrocitye EC so Inactive (ful) Patent Application Publication May 13, 2010 Sheet 3 of 15 US 2010/0120842 A1 Figure 3 Cell Count -- SabComeline -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 -3.5 Log Conc (M) Patent Application Publication May 13, 2010 Sheet 4 of 15 US 2010/O120842 A1 †7?un61– (sÁeq)eu?L eu||euOoqes:Kessy?aunou?MousoueuunH No. eSegueno eSeeJoulueOue Patent Application Publication May 13, 2010 Sheet 5 of 15 US 2010/O120842 A1 i. Patent Application Publication May 13, 2010 Sheet 6 of 15 US 2010/O120842 A1 Figure 6 LOCOmotor Activity: Acute Dosing 12OO -0-Vehicle - 0.05 mg/kg 6OO 400 5 1 O 15 2O 25 3O Time Period (min) Patent Application Publication May 13, 2010 Sheet 7 of 15 US 2010/O120842 A1 Figure 7 400 -- vehicle -- 0.01 mpk 350 0.05mpk era. O Ye' wC 300 . D 3. 25 > Os O 200 s CD s 50 100 Time Period (days) Patent Application Publication May 13, 2010 Sheet 8 of 15 US 2010/O120842 A1 Figure 8 Forced Swim Test: Acute Dosing immobility Swimming Climbing Patent Application Publication May 13, 2010 Sheet 9 of 15 US 2010/O120842 A1 Figure 9 Novelty Suppressed Feeding: Chronic 400 | 350 300 250 200 150 100 50 water 0.01 0.05 | reatment Patent Application Publication May 13, 2010 Sheet 10 of 15 US 2010/0120842 A1 Figure 10 Sabcomeline Preference for Novel Object (visits) 0.9 0.8 0.7 0.6 O.5 0.4 0.3 O2 0.1 O.O Vehicle 0.05 Treatment (mg/kg) Patent Application Publication May 13, 2010 Sheet 11 of 15 US 2010/0120842 A1 S' i. E.s: 53. Patent Application Publication May 13, 2010 Sheet 12 of 15 US 2010/O120842 A1 C/D C O S O CD Z : C CD 21 : Patent Application Publication May 13, 2010 Sheet 13 of 15 US 2010/O120842 A1 : p < 0.05 Vehicle Fluoxetine 5.0 Sabcomeline 0.01 Combination Vehicle 10000 ... Fluoxetine 9000 Sabcomeline 8000 x: Ombination 7000 x 6000 5000 4000 C C 3000 X C XSS 2000 XXXx: &8: 88 8 1000 x Dorsal Hippocampus Ventral Hippocampus Patent Application Publication May 13, 2010 Sheet 14 of 15 US 2010/O120842 A1 Figure 14 C a p to p r il D on ep e Z il A V G Neur on a Differentiation (T U J 1 ) 38 - C a p to pril D one pezil 49 or IC a p to pri a. 5 8 s-iss D one pezi - 1 1 0 1 00 O 7 0 6 0. s 5 0. s 4 O 3 O 201 O O - 10 10 -8.5 1 0 -8.0 1 0 -7.5 1 0 - 7.0 1 0 -6.5 1 0 - 6.0 1 O -5.5 1 0 -5.0 1 0 - 4.5 1 0 -4.0 C on c (M) Patent Application Publication May 13, 2010 Sheet 15 of 15 US 2010/0120842 A1 Figure 15 B u s p iro n e + D on ep e Z il A stro cyte Differentiation (G F A P ) 1 0 -B us p iro n e D one pezil 1 O O rth B us pir one 9 O 8 O 7 O 6 O 5 O 4 O 3 O 2 O 1 O O - 10 1 0 -8.5 1 0 - 8.0 1 0 -7.5 1 0 -7.0 1 0 - 6 - 5 1 0 -6.0 1 0 - 5.5 1 0 -5.0 1 0 -4.5 1 0 - 4.0 C on c (M) US 2010/0120842 A1 May 13, 2010 NEUROGENESIS BY MUSCARINC 0005 Five sub-types of muscarinic receptors have been RECEPTORMODULATION characterized, and are designated m1, m2, m3, mak, and mS. m1 receptors are found in the CNS and peripheral ganglia, m2 CROSS-REFERENCES TO RELATED receptors are found on cardiac cells and in the brainstem, m3 APPLICATIONS receptors are found in Smooth muscle, endocrine (e.g., the pancreas) and exocrine glands (e.g., the lacrimal glands), and 0001 Under 35 U.S.C. S 120this application is a divisional the cerebral cortex, ma receptors are found primarily in the application of U.S. application Ser. No. 1 1/467,527, filed neostriatum, and m5 receptors are found primarily in the Aug. 25, 2006, now pending, which claims benefit of priority Substantia nigra. Muscarinic receptors are G-protein coupled under 35 U.S.C. S 119(e) to U.S. Provisional Patent Applica receptors (GPCRs), with the activity of the m1, m3 and m3 tions 60/711,846, filed Aug. 26, 2005; 60/727,127, filed Oct. receptors mediated by the phosphoinositide second-messen 14, 2005; 60/738,133, filed Nov. 17, 2005; and 60/803,826, ger system, and the m2 and m4 receptors linked to the ade filed Jun. 2, 2006; all of which are hereby incorporated by nylate cyclase second messenger system. reference as if fully set forth. 0006 Compounds with activity against muscarinic recep tors have been studied for the treatment of conditions linked FIELD OF THE DISCLOSURE to cholinergic dysfunction, such as Alzheimer's Disease, which is associated with the degeneration of cholinergic neu 0002 The instant disclosure relates to methods for treating rons in the forebrain. Clinical testing has revealed a high diseases and conditions of the central and peripheral nervous degree of debilitating, dose-limiting side effects associated system by stimulating or increasing neurogenesis via modu with compounds active against the m2 and m3 receptor Sub lation of muscarinic receptor activity, including via inhibition types, including cardiovascular and gastrointestinal side of acetylcholine esterase (AChE) activity in combination effects. In contrast, compounds that are selective for ml with another neurogenic agent. The disclosure includes meth receptors, or m1 and m4 receptors have generally been found ods based on the application of a neurogenesis modulating to have better clinical profiles, with enhanced efficacy and agent having activity against muscarinic receptors and/or an decreased side effects. To date, there is has been little research AChE inhibitor with another neurogenic agent to stimulate or regarding the use of muscarinic compounds to treat diseases activate the formation of new nerve cells. not characterized by or Substantially resulting from cholin ergic dysfunction. BACKGROUND OF THE DISCLOSURE 0007 Acetylcholinesterase, or AChE, is also known as 0003) Neurogenesis is a vital process in the brains of ani erythrocyte (or RBC) cholinesterase and acetylcholine mals and humans, whereby new nerve cells are continuously acetylhydrolase. It is classified at EC 3.1.1.7 and is found in generated throughout the lifespan of the organism. The newly various locations, including the blood and neural synapses. born cells are able to differentiate into functional cells of the AChE catalyzes hydrolysis of the neurotransmitter acetyl central nervous system and integrate into existing neural cir choline into choline and acetic acid where acetylcholine is a cuits in the brain.
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