nicotinic receptor therapeutics & drug dependence

Nicotinics Monthly

Nicotinic Receptor Therapeutics & Drug Dependence

In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity

February 2011 Edition(Featuring information published: Feb 4th - Mar 10th)

Next issue April 8th (approx)

Nicotinics Monthly

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Nicotinics MonthlyExecutive summary of new activity

February 2011 - Key activity around the α7 receptor

• TC-5619 - Phase 1 Alzheimer’s study now fully enrolled: Targacept has been evaluating TC-5619 in Phase 2a studies of ADHD and CIAS. Positive top line CIAS data were reported in the December issue of UpdatesPlus; ADHD data are expected very shortly. In February Targacept announced through clinicaltrials.gov that a Phase 1 Alzheimer’s disease study is also now fully enrolled and that data remains on track to read out in Q2 2011.

• PAM assay from Abbott: Abbott has displayed an interest in PAMs. A recent Abbott patent claims screening tools for the identification of α7 PAMs (WO 2009/003074). Company researchers have now published one assay in detail. In particular the assay is compatible with HTS for Type II PAMs (ie those that increase peak response and slow desensitization).

• α7 receptor agonists as potential treatments of thrombocytopenia: Chronic immune thrombocytopenic purpura (ITP) and drug induced thrombocytopenia require new treatment approaches. The potential market for new treatments may exceed $0.5 billion. New research has shown α7 antagonism blocks platelet differentiation; extending this finding by demonstrating agonist-induced differentiation would support further expansion of the nicotinics field into the treatment of platelet diseases.

• Can α7 receptor agonists improve mortality and morbidity after cardiac arrest? Delayed mortality and morbidity after cardiac arrest is due in part to global cerebral ischemia. New research suggests that α7 agonists can limit cerebral inflammation and hippocampal cell damage.


February 2011 - Key activity around the α4β2 receptor

• New Phase 1 study of TC-5214 announced: We have learned that Quintiles is looking for 32 patients to include in a Phase 1 study of TC-5214. The study will assess the safety, tolerability and pharmacokinetics of the candidate in elderly patients. We believe that this study simply reflects filling requirement, allowing data to be included on an eventual product label on special populations. Data in the elderly would however be useful given the prevalence of depression in this cohort.

• GSK/Targacept alliance terminated as GSK realigns CNS activities: Targacept and GSK have been collaborating since 2007 in various CNS diseases. GSK has now terminated its alliance with Targacept due to GSK’s strategic changes in the neurosciences area in 2010. This is not expected to present a major problem to Targacept given its evolution as a company over recent years. Companies interested in in-licensing candidates emerging from the collaboration may stand to benefit; alternatively Targacept should hopefully be in a position to advance these candidates unilaterally if necessary.


February 2011 - Key activity around other nicotinic receptors

• Researchers identify bupropion analogues with α3β4* affinity and smoking cessation potential: Researchers at the Research Triangle Institute have identified analogues of the smoking cessation product, bupropion. These analogues have been suggested to act through the modification of dopamine and norepinephrine uptake as well as stimulation of α3β4* receptor activity.


January 2011 - Key activity around smoking cessation

• Varenicline study opens in paediatric patients: Smoking remains a serious problem in adolescents. In an attempt to help address this problem Pfizer has opened a study of 300 adolescents smokers. The primary end-point will read out in Aug 2013. This study has the additional advantage for Pfizer in that it could result in a paediatric extension.

• Johnson & Johnson opens new nicotine replacement therapy study: The product being evaluated in the study (NCT01296698) is not disclosed. Of note the 1500 subject study is apparently a pharmacy based one. This design has been selected to make the study more naturalistic. Initial screening and data collection will be conducted by the pharmacist.

• NicVax extension study opens: Nabi, in partnership with GSK, is currently conducting two Phase 3 registration trials of NicVax. This vaccine generates antibodies to nicotine which are hoped to prevent temporary lapses developing into full relapse by neutralizing nicotine. Both studies are now fully enrolled and should read out Q1 2012. An extension study (NCT01304810) has now been advanced. This is simply an observational study and will monitor antibody persistence.

• Duke University evaluates new smoking cessation strategy: Individuals who appear unlikely to abstain on nicotine replacement therapy alone will be randomized to receive varenicline alone or combined with bupropion. The remarkably large study (NCT01303861) is recruiting 1500 people and is due to read out H2 2012.


January 2011 - Key activity around drug dependence (excluding nicotine)

• Omeros expands its drug addiction portfolio by in-licensing PDE7 inhibitors from Daiichi: Omeros has an addiction program, initially focused on the development of PPARγ agonists. Last year Omeros received an exclusive licence to develop Daiichi's PDE7 inhibitors as treatments for movement disorders, such as Parkinson's disease. Now Omeros has now announced that it is investigating these inhibitors for the treatment of addiction.

• NK1 antagonists for the potential prevention of relapse in recovering alcoholics: Relapse is a common event in recovering alcoholics. This can be induced by alcohol cues or stressful life events. NK1 antagonists have been developed for anxiety and depression. Data has now shown that this class may be of use in preventing stress induced relapse in alcoholics.

• Muscarinic M4 receptor agonists as candidates for cocaine addiction? Genetic deletion of the M4 receptor has been shown to increase cocaine self-administration. This suggests that the development of agonists as candidate treatments of addiction is warranted.

Nicotinics MonthlyThis Month’s activity around the α7

receptor

Nicotinics Monthly

Pipeline Overview – α7 ligands

Preclin Phase 1 Phase 2 Phase 3

Alzheimer’s - Xytis no longer trading?Xytis – XY 4083

Targacept – TC-6987 Neuroderm - ND0801Asmacure - ASM-024Novartis - AQW051Targacept - TC-5619EnVivo - EVP-6124Roche - RG3487 (RO-5313534)

Positive Allosteric ModulatorsAgonists

Ph 2a Completion Q1 2011 (CIAS; ADHD)

Asthma/Diabetes ADHDAsthmaCIASCIAS/ADHD/Alzheimer’s(?)Alzheimer’s/CIASAlzheimer’s

Ph 2 Opened: Q2 2010

Ph 2 opened 2010


Ph 2b Completion: Q1 2011 (AD)

Ph 2b Completion: Q3/Q1 2011 (AD/CIAS)


Nicotinics Monthly

Pipeline Overview – α7 ligands

Pipeline changes for February 2011

•No Changes

Nicotinics MonthlyTargacept discloses a few further details on

Phase 2 TC-6987 studies

• The January issue of UpdatesPlus featured the initiation of Targacept’s Phase 2 studies of TC-6987 in asthma and diabetes.

• The asthma study has now been posted on clinicaltrials.gov (NCT01296087). – As previously reported, mild to moderate asthmatics are being enrolled into this US randomized placebo

controlled trial. – During an initial 4 week run-in period, patients will receive low-dose inhaled corticosteroid and cease taking

their current asthma medication.– On top of this baseline, patients will receive TC-6987 at 100mg for the first day of dosing followed by 50mg for

a further 4 weeks. Placebo will be dosed in a control arm. As is standard for asthma studies, improved FEV will be the primary end point.

– We now know that TC-6987 will be dosed orally contrasting with ASM-024, an inhaled nicotinic agent in development for asthma. In addition, individuals using strong P450 3A4 (CYP3A4) inhibitors are being excluded suggesting this enzyme is responsible for the metabolism of TC-6987.

• The diabetes study has also been posted (NCT01293669). – On the entry TC-6987 is described as an open channel stabilizer. In vivo data were also disclosed and

particularly that TC-6987 improved both metabolic parameters (plasma glucose, triglyceride, and Hb1Ac) and reduced inflammatory mediators (TNF-α).

– Patients will receive TC-6987 or placebo as a monotherapy after a 4 week wash-out. Dosing will be with 20mg for the first day dropping to 10mg for the remainder of the dosing period (note that the dose is considerably lower than for the asthma study).

– Fasting plasma glucose will be the primary measure.

Nicotinics MonthlyThrombocytopenia: A group of platelet

diseases potentially treatable by α7 agonists?

• Thrombocytopenia is defined as an abnormally low platelet level and is associated with clotting disorders.

• The common autoimmune disease, immune thrombocytopenic purpura (ITP) is caused by platelet antibodies. ITP presents as:

– Acute self-limiting ITP which is primarily a paediatric condition.

– Chronic ITP, an orphan disease affecting 3-5/100,000 adults.

• Thrombocytopenia can also arise as a side effect of cytotoxic agents and ribavirin (used in HCV treatment)

• Treatment of thrombocytopenia has changed in the past decade with the current focus on two new thrombopoietin mimetics (TPO): romiplostim (Nplate; an injectable peptide) and eltrombopag (Promacta; an orally small molecule).

• Romiplostim is disadvantaged by its peptidic nature while eltrombopag carries a black box warning of hepatotoxicity.

• Rodman & Renshaw has forecast sales of $510 million by 2012 for Promacta assuming approval for oncology and HCV. So far sales remain at $50 million with indications limited to ITP.

• With Promacta having failed to live up to expectations there is potentially space for new platelet stimulation agents and recent data suggests nicotinic agents could fill this niche.

Veltuzumab (Immunomedics)

S-888711 (Shionogi)

2285921(GSK)

No Phase 3 candidates

Few pipeline candidates target thrombocytopenia

Phase 2 Phase 3

Nicotinics MonthlyPlatelets as a new target for α7 nicotinic

agonists?

• In addition to thrombopoietin receptors, components of the cholinergic system have been detected in platelet precursors (megakaryocytes), and platelets themselves.

• Moreover cholinergic agonists have been shown to modulate megakaryopoiesis and stimulate megakaryocyte proliferation.

• In 2010 Schedel et al reported the expression of α7 receptors on platelets.

• The same group has now reported that MLA, used at concentrations known to antagonize α7, blocks megakaryocyte differentiation (Thornton et al. 2011; see inset).

• This suggests that α7 agonists may enhance differentiation offering a new approach to the treatment of thrombocytopenia.

Megakaryoblasts were stimulated by the differentiation factor, TPA. This caused increased expression of the megakaryocyte marker, CD61. This was reduced by both nicotine and MLA

The next obvious study would be to determine whether an α7 agonist is able to stimulate platelet generation and to compare this to the effect of a TPO.

Nicotinics MonthlyNew data suggests α7 agonists may limit

post resuscitation cerebral ischemic damage

• In the US, according to the AHA, emergency medical personnel treat ≈300,000 victims of out-of-hospital cardiac arrest each year.

• Sasson et al, 2009 reported that 24% of those treated survived to hospital admission.

• However, <8% of victims survived to discharge. Delayed mortality and morbidity is due in part to global cerebral ischemia following successful resuscitation.

• Using a rodent model, Norman et al have now reported the involvement of α7 receptors in cerebral ischemia.

• The authors report that cardiac arrest/cardiopulmonary resuscitation (CA/CPR) increased hippocampal proinflammatory mediators. Elements of the cholinergic system were also down-regulated.

• Treatment with GTS-21 reversed the elevation in hippocampal IL-6 and microglial number (top panel) suggesting anti-inflammatory activity. This was reflected in reduced hippocampal neural cell damage (lower panel). Each of these changes was inhibited by mecamylamine

Microglia marker, MAC1 was reduced in rodents subject to CA/CPR and treated with GTS-21 daily post arrest

Fluro-Jade levels were also reduced by GTS-21 reflecting reduced neural damage

Effect of GTS-21 on hippocampal inflammation and neural death following CA/CPR

Nicotinics MonthlyThis Month’s activity around the α4ß2

receptor

Nicotinics Monthly

Smoking Cessation (patch)CognitionIBS

Pipeline Overview – α4ß2 ligands


Pfizer – Varenicline (LCM)

PAM

*Mecamylamine is considered a poorly selective nicotinic ligand

AntagonistsPartial Agonists

Depression

Ph 2b ? Starting in Q1 2011

Targacept - TC-5214 Depression•NDA H2 2012•MAA 2015

Ph 2 (mono) & Phase 3 (add on) Started Mid-2010

Ph 2a

Ph 2b Completed 2008

Ph 2b Completed 2008 - presumed terminated

Abbott- A-969933/NS9283

Suven - SUVN-F90101; SUVN-F90201Suven - SUVN-911Amgen - Unnamed cpds

Targacept/GSK - TC-5653 (dual α4ß2/α6) Targacept - AZD3480 Backups

Abbott/NeuroSearch – ABT-560Targacept – TC6499

Targacept/AstraZeneca (AZD1446/TC-6683Pfizer - CP-601927

AstraZeneca – ispronicline (AZD3480/TC-1734)Abbott/NeuroSearch - ABT-894 (Sofinicline)

CoMentis – ATG-3 (Mecamylamine)*AGI - AG-004 (Mecamylamine)*Pfizer – Varenicline

Abbott - ABT-089 (Pozanicline)

Alzheimer’s

ADHDADHD

ADHD/Alzheimer’s

AMD

Alzheimer’s

Diarrhea

Nicotinics Monthly

Pipeline Overview - α4ß2 ligands


• No changes

Nicotinics MonthlyPhase 1 study of TC-5214 about to start in

the elderly

• The Phase 3 program, RENAISSANCE, studying TC-5614 as a candidate treatment for depression is now well underway.

• We have recently learned that the CRO, Quintiles is looking for 32 patients to enrol into a Phase 1 study of TC-5214.

• The trial, which will take place at a single site in Sweden, is expected to be completed by April this year and will assess the safety, tolerability and pharmacokinetics of multiple oral doses of TC-5214 in medically stable patients, more than 65 years old.

This study probably reflects a filing requirement, evaluating the safety of TC-5214 in special populations including the elderly. It should be noted however that depression is an especial problem in the elderly. The generation of efficacy data subsequent to this study could help promote the sale of TC-5214 post-launch.

Nicotinics MonthlyTargacept and GSK go their separate ways

as GSK realigns its activity within the neurosciences

• Targacept and GSK have been collaborating since 2007 in five therapeutic areas - pain, smoking cessation, addiction, obesity and Parkinson's disease.

• The collaboration produced TC6499 for the treatment of pain however this development was stopped in 2009 due to an insufficient therapeutic margin. Targacept has since switched indications to IBS.

• In addition the companies were developing a dual α4ß2/α6 agent which we believe was being targeted towards smoking cessation. Activities around this indication have drawn in milestone payments for Targacept in the past.

• GSK has now terminated its alliance with Targacept due to GSK’s strategic changes in the neurosciences area in 2010.

• While this is obviously not ideal for Targacept it has gained full rights to the programmes and related candidates that were within the alliance. This opens up the possibility of new partnering opportunities.

• Since the alliance was opened Targacept has evolved as a company with market entry potentially on the horizon. Revenue generated by the launch of molecules such as TC-5214 means that Targacept should hopefully be in a good position to continue development of assets emerging from the GSK partnership even if it doesn’t find another partner to replace GSK.

Nicotinics MonthlyThis Month’s activity around other subtypes

Nicotinics MonthlyResearchers identify bupropion analogues

with α3β4*affinity and smoking cessation potential

• Researchers at the Research Triangle Institute have been developing analogues of bupropion for the treatment of nicotine dependence.

• These analogues have been suggested to act through the modification of dopamine and norepinephrine uptake as well as stimulation of cholinergic receptor activity.

• Further activity has now been reported around a 2-(substituted phenyl)-3,5,5-trimethylmorpholine scaffold.

• Analogues from this series were profiled in vitro and then evaluated in two animal models: nicotine induced antinociception and nicotine-conditioned place preference. These are assays for the acute and reward effects of nicotine.

• Two molecules were selected as being of especial interest as smoking cessation candidates.

Chemistry In vitro profile(IC50 nM)

In vivo activity(AD50 mg/kg)

R1 R2 DA NE α3β4* Tail-flick

CPP

bupropion 660 1900 1.8 1.2 0.35

5e CH3 C2H5 44 24 0.79 0.029 0.025

5f CH3 C3H7 61 13 0.98 0.056 0.03

Nicotinics MonthlyThis Month’s activity around smoking

cessation/nicotine dependencePharmacologic approaches

Nicotinics Monthly

Pipeline Overview Smoking cessation/nicotine dependence


Pfizer - Varenicline (LCM)

Pfizer - Chantix/Champix

Marketed

Cytos/Novartis - NIC002

Nabi Pharma - NicVax Phase 3 studies to complete 2012

Acrux - Nicotine MDTSAradigm - ARD-1600Cary Pharmaceuticals - QuitPak

Celtic Pharma -TA-NIC

Independent Pharma - Niccine

GSK - Niquitin CQ

GSK - Bupropion

Nicotinics Monthly

Pipeline Overview – Smoking Cessation


•No Changes

Nicotinics Monthly

Pfizer opens US paediatric varenicline study

• According to data from 1999-2004 (CDC National Health Statistics Reports, 2009), 37% of adolescents who smoked were daily smokers and 33% smoked ≥6 cigarettes per day.

• 2009 figures (CDC, Health, United States, 2010) show a remarkable fall in the rate of adolescent smoking however this trend has flattened out and there remains a clear need to address smoking cessation in younger individuals.

• With these statistics in mind it is of interest to note that Pfizer has opened a new varenicline study in adolescents (NCT01312909).

• The US study will enrol 300 adolescents who smoke at least 6 cigarettes/day.

• The study is similar to varenicline registration studies. Of note however, a half dose of varenicline will be used in lighter individuals.

• The primary end-point will read out in Aug 2013

Adolescent smoking remains high in the US

Although success in this study would be of potential use in reducing the rate of adolescent smoking, it would also benefit Pfizer. Not only could it increase the size of the market, the study could also support a paediatric extension for varenicline.

Nicotinics MonthlyStudy opens to evaluate varenicline for

smoking reduction in those not ready to quit

• Nicotine replacement therapies were initially approved in order to help immediate smoking cessation. However in 2005 regulations in some regions changed to allow the use of such therapies as a stepping stone to quitting.

• A 2007 systematic review suggested that a substantial reduction in smoking improved several cardiovascular risk factors, and respiratory symptoms (Pisinger & Godtfredsen, 2007).

• Consequently, regulatory authorities and particularly those in the UK have allowed the use of NRT to help reduce or temporarily stop smoking. Indeed a recent survey of English smokers has revealed that 28% of smokers use nicotine replacement therapy for this purpose.

• Of interest New Jersey researchers have now opened a study (NCT01308736) of 60 individuals to determine whether varenicline can reduce smoking in individuals not wishing to quit.

This study is of interest given that varenicline has a boxed warning. If the study does demonstrate a reduction in the number of cigarettes smoked without a significant reduction in abstinences we ask what the implications may be? The study is too small to bring about change on its own but a larger study could pressure regulators to approve varenicline as a smoking reduction strategy. We doubt whether this would occur unless high risk patients were to be studied, ideally with clinical outcomes measures.

Nicotinics MonthlyArbi Group and Italian Antismoking League

complete E-cigarette studies

• The Arbi Group, an Italian electronic cigarette retailer, in collaboration with the Italian anti-smoking league, opened a number of studies in 2010.

• The studies (NCT01188239; NCT01194583; NCT01164072) were investigating the ability of E-cigarettes to reduce smoking.

• These studies are no longer recruiting and we believe that data is now available. Smokers with no

intention to quit

Base Study visitto monitor

wk2 Wk4 wk6 wk8 wk10 wk12

1O Outcome Measures•Sustained 50% reduction in cigarettes at each visit•Sustained smoking abstinence at wk12

2O Outcome Measures include•Sustained 80% reduction in cigarettes at each visit•Sustained smoking abstinence at wk24•Withdrawal suppression•Cravings reduction•Adverse events

Nicotinics MonthlyThis Month’s activity around drug

dependence (excluding nicotine)Pharmacologic approaches

Nicotinics Monthly

Pipeline Overview Drug dependence (excluding nicotine)

Phase 1 Phase 2 Phase 3 Marketed

Alkermes (ALKS 33)

Alkermes (VIVITROL)

Lundbeck/BioTie (Nalmefene) MAA Expected H2 2011

Lilly (LY-2456302)

BioTie (Nepicastat; SYN-117)

Lilly (OprA)

Catalyst (CPP-109)

Reckitt Benckiser (Suboxone Film)

GSK (618334)

BioDelivery (buprenorphine/naloxone)

Forest/Meram (CAMPRAL/AOTAL)

Generic Suboxone (buprenorphine/naloxone)

Generic Subutex (buprenorphine)

Orexa (Buprenorphine/Naloxone)

Omeros (PPARγ ligands)

AIKO-150 (AIKO)

NanoBUP (Nanotherapeutics)

Titan (Probuphine)

Pivotal Phase 2b started; IND H2 2012?

Nicotinics MonthlyPipeline Overview – Drug dependence

(excluding nicotine)


•No Changes

Nicotinics MonthlyD&A Pharma is about to file reformulated

treatments of alcohol and opiate addiction

• Sodium oxybate has been marketed in Italy for several years as a liquid-formulation for alcoholism. This product is unfortunately also used as a street drug and therefore has significant misuse potential.

• D&A Pharma is addressing this through the development of SMO-IR, an immediate-release, thin-pellet formulation.

• The company expects to file in Europe in 2011 having demonstrated bioequivalence of SMO-IR with sodium oxybate. A granule formulation may follow on from SMO-IR

• At the same time the company has reported that it also intends to file an “undisclosed dual µ/κ opioid agonist” for the treatment of opiate addiction. This product is presumed to be a reformulation of suboxone.

Nicotinics MonthlyOmeros expands its drug addiction portfolio

by in-licensing PDE7 inhibitors from Daiichi

• Omeros has an addiction program, initially focused on the development of PPARγ agonists. Pilot human and preclinical data suggest that this class may be most effective in the treatment of addiction to opioids, alcohol and nicotine. Efficacy as a treatment of psychostimulant addiction (cocaine and methamphetamine) is expected to be less impressive.

• Last year Omeros received an exclusive licence to develop Daiichi's PDE7 inhibitors as treatments for movement disorders, such as Parkinson's disease.

• Now Omeros has now announced that it is investigating these inhibitors for the treatment of addiction, thus expanding their activities within the drug dependence field.

• PDE7 appears to modulate the dopaminergic system and according to Omoros, PDE7 inhibitors have been shown to reduce cocaine self-administration, inhibit cue and stress induced relapse, and facilitate drug abstinence in models of cocaine addiction.

• Under the amended deal, milestone payments from Omeros to Daiichi have increased from $23.5 million to $30.2 million.

Nicotinics MonthlyNK1 antagonism reduces stress-induced

reinstatement of alcohol intake

• NK1 antagonism has previously been shown to prevent the rewarding effect of morphine. Schank et al now report the effect of this therapeutic class on alcohol consumption.

• Previous studies have implicated the potential efficacy of NK1 antagonists in treating alcoholism however it is not clear if such agents would suppress ongoing excessive alcohol use, prevent relapse, or both.

• In their paper published in Psychopharmacology, the NIH group reports that LY822429 fails to modify alcohol self-administration in rodents suggesting no effect on excessive alcohol use.

• In contrast LY822429 blocked stress-induced reinstatement of alcohol consumption (inset). Cue-associated reinstatement was not however affected by NK1 antagonism.

• NK1 antagonists have been developed for anxiety and depression. The present data suggests that this class may be useful in treating recovering alcoholics in times of stress. This class may complement Naltrexone that reduces cue induced re-instatement.

Nicotinics MonthlyNew data suggests that muscarinic M4

agonists may be of benefit to cocaine addiction

• In 2010 we reported on a series of dual α7/M4 agonists with analgesic and anti-inflammatory properties.

• To our knowledge the M4 class remains an underexploited therapy area; to date no M4 agonists have entered the clinic.

• Now we report that this class may be of benefit in treating addiction as well as inflammation/pain.

• Previous studies have shown M4 knock-out to enhance D1 receptor induced motor activity.

• In the March issue of Psychopharmacology Schmidt et al have now reported that M4 receptor knock-out is associated with greater cocaine self-administration under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement .

− Panel A of the inset demonstrates that cocaine self-administration was higher under a FR1 schedule in M4 knock-outs.

− Panel B demonstrates that higher breaking points were reached in the PR schedule. Using this schedule, the number of responses required to earn a cocaine reward was gradually increased until the breaking point where mice no longer attempted to earn a reward. This measure provides an index of motivation.

• In addition, this group demonstrated that cocaine induced dopamine efflux in the nucleus accumbens and hyperlocomotion was increased in knock-out mice.

• Having established a proof of concept for targeting M4 receptors, the development of agonists as candidate treatments of addiction is warranted.

Nicotinics Monthly

Annex: Content identified for this edition

Nicotinics Monthly

Stakeholders tracked in UpdatesPlus

• Abbott • Acrux• AGI • AIKO • Alza (J&J)• Reckitt Benckiser• American Snuff• Omeros• Aradigm• Asmacure• AstraZeneca • BAT• Bayer • BioTie• Cary Pharmaceuticals• Catalyst• Celtic Pharma

Nicotinics Monthly

Stakeholders contd.

• CoMentis • Cornerstone Therapeutics (Critical Therapeutics) – Portfolio licensed

by Targacept• Cytos• EnVivo• Eli Lilly• Forest• GSK • Independent Pharma• Johnson & Johnson• Lundbeck• Mitsubishi• Neuroderm• NeuroSearch• Nabi Pharma• Nanotherapeutics

Nicotinics Monthly

Stakeholders contd.

• Niconovum• Novartis • Pfizer • Philip Morris Int• Philip Morris USA• ReceptoPharm• Reckitt Benckiser• Reynolds American• Roche (now including Memory Pharma)• Sanofi-Aventis• Swedish Match• Servier • Siena Biotech• Suven• Targacept• Titan• Wyeth (now Pfizer) • Xytis (website down in July – possibly ceased trading)

Nicotinics MonthlyKey Papers

1Reprints available from LeadDiscovery

Carroll et al.1

Synthesis of 2-(Substituted Phenyl)-3,5,5-trimethylmorpholine Analogues and Their Effects on Monoamine Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine.

J Med Chem. 2011 Mar 10;54(5):1441-1448

Gopalakrishnan et al.1

Functional Characterization and High-Throughput Screening of Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors in IMR-32 Neuroblastoma Cells.

Assay Drug Dev Technol. 2011 Feb 10

Norman et al. 1

Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic {alpha}7 Nicotinic Receptors.

J Neurosci. 2011 Mar 2;31(9):3446-52.

Schank et al. 1 Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429. Psychopharmacology (Berl). 2011

Feb 22

Schmidt et al. 1 Increased cocaine self-administration in M(4) muscarinic acetylcholine receptor knock-out mice. Psychopharmacology (Berl). 2011

Mar 5

Thornton et al. 1 Cholinergic drugs inhibit in vitro megakaryopoiesis via the alpha7-nicotinic acetylcholine receptor. Platelets. 2011 Mar 9

Nicotinics Monthly

Selected Papers

Alkadhi et al. Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine. Int J Neuropsychopharmaco

l. 2011 Feb 28:1-11

Berlin et al.Adjustment of nicotine replacement therapies according to saliva cotinine concentration: the ADONIS* trial-a randomized study in smokers with medical comorbidities.

Addiction. 2011 Apr;106(4):833-843.

Bobes et al. Pregabalin for the discontinuation of long-term benzodiazepines use: An assessment of its effectiveness in daily clinical practice. Eur Psychiatry. 2011 Feb 18

Boudrez et al. Effectiveness of varenicline as an aid to smoking cessation: results of an inter-European observational study. Curr Med Res Opin. 2011 Ap

r;27(4):769-75

Cahill et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011 Feb 16;2

Catz et al. Adherence to Varenicline in the COMPASS Smoking Cessation Intervention Trial. Nicotine Tob Res. 2011 Feb

24

de Bruin et al.The 5-HT(6) serotonin receptor antagonist SB-271046 attenuates the development and expression of nicotine-induced locomotor sensitisation in Wistar rats.

Neuropharmacology. 2011 Feb 15

Nicotinics Monthly

Selected Papers

Echeverria et al. Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice. J Alzheimers Dis. 2011 Feb

14

Grassi et al. Effectiveness of varenicline for smoking cessation: A 1-year follow-up study. J Subst Abuse Treat. 2011 Feb 22

Hendrickson et al. Nicotinic acetylcholine receptors containing the α4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption. Channels (Austin). 2011 Ma

r 1;5(2)

Huang et al. Computational design of a thermostable mutant of cocaine esterase via molecular dynamics simulations. Org Biomol Chem. 2011 Ma

r 4

Hutcheson et al.Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward.

Behav Pharmacol. 2011 Apr;22(2):173-81.

Kaniaková et al. Dual effect of lobeline on α4β2 rat neuronal nicotinic receptors. Eur J Pharmacol. 2011 Mar 1

Kox et al. Effects of the αα7nAChR Agonist GTS-21 on the Innate Immune Response in Humans. Shock. 2011 Feb 22

Nicotinics Monthly

Selected Papers

Kucinski et al. Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia. Curr Pharm Biotechnol. 2

011 Mar 1;12(3):437-48.

Levin et al. Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 20

11 Feb 8

Lien et al. Nicotine Promotes Cell Migration Through Alpha7 Nicotinic Acetylcholine Receptor in Gastric Cancer Cells.

Ann Surg Oncol. 2011 Feb 23

Liu et al. Vagus nerve stimulation inhibits heroin-seeking behavior induced by heroin priming or heroin-associated cues in rats.

Neurosci Lett. 2011 Mar 6

Lykhmus et al.Antibodies against Extracellular Domains of alpha4 and alpha7 Subunits Alter the Levels of Nicotinic Receptors in the Mouse Brain and Affect Memory: Possible Relevance to Alzheimer's Pathology.

J Alzheimers Dis. 2011 Feb 14

Lê et al. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats.

Psychopharmacology (Berl). 2011 Feb 12

Minozzi et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2011 Feb 16;2

Nie et al. Nicotine Decreases Beta-Amyloid Through Regulating BACE1 Transcription in SH-EP1-α4β2 nAChR-APP695 Cells.

Neurochem Res. 2011 Feb 19

Nicotinics Monthly

Selected Papers

Osanai & Lee Nicotine-mediated suppression of the retinoic acid metabolizing enzyme CYP26A1 limits the oncogenic potential of breast cancer. Cancer Sci. 2011 Mar 3

Pivavarchyk et al. Indolizidine (-)-235B' and related structural analogs: Discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [(3)H]dopamine release.

Eur J Pharmacol. 2011 Mar 1

Ramdurg et al. Sexual Dysfunction among Male Patients Receiving Buprenorphine and Naltrexone Maintenance Therapy for Opioid Dependence. J Sex Med. 2011 Mar 2

Shahab et al. Acceptability and effectiveness for withdrawal symptom relief of a novel oral nicotine delivery device: a randomised crossover trial.


Sjoberg & Saint A Single 4 mg Dose of Nicotine Decreases Heart Rate Variability in Healthy Nonsmokers: Implications for Smoking Cessation Programs.

Nicotine Tob Res. 2011 Feb 24

Nicotinics Monthly

Selected Papers

Stapleton & Sutherland Treating heavy smokers in primary care with the nicotine nasal spray: randomized placebo-controlled trial.

Addiction. 2011 Apr;106(4):824-32

Tanabe et al. Nicotine effects on default mode network during resting state. Psychopharmacology (Berl). 2011 Feb 18

Thanos et al. D-cycloserine facilitates extinction of cocaine self administration in rats. Synapse. 2011 Feb 25

Volkow et al. Reduced Metabolism in Brain "Control Networks" following Cocaine-Cues Exposure in Female Cocaine Abusers.

PLoS One. 2011 Feb 23;6(2):e16573.

Walker et al.DOES IMPROVED ACCESS AND GREATER CHOICE OF NICOTINE REPLACEMENT THERAPY AFFECT SMOKING CESSATION SUCCESS? FINDINGS FROM A RANDOMISED CONTROLLED TRIAL.

Addiction. 2011 Mar 3

Watson et al. A pilot study of the effectiveness of D: -cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects.


Weiner et al. 1 Varenicline for smoking cessation in people with schizophrenia: a double blind randomized pilot study.

Schizophr Res. 2011 Mar 2

Wouda et al. Varenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control.


Yang et al.Functional Nicotinic Acetylcholine Receptors Containing {alpha}6 Subunits Are on GABAergic Neuronal Boutons Adherent to Ventral Tegmental Area Dopamine Neurons.

J Neurosci. 2011 Feb 16;31(7):2537-48.

Nicotinics Monthly

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