Harvard University Extension School CHEM E-120

1. Harvard University Extension SchoolCHEM E-120 ChantixTM Varenicline Tartrate

2. Substance Abuse Substance abuse is a worldwide problem costing an estimated $181 billion in the USA alone . 22.6 million persons in the USA aged 12 or older in 2006 were classified with substance dependence or abuse (DSM-IV criteria) in the past year (9.2 percent of the national population) 15.6 million were dependent on or abused alcohol alone 3.2 million were classified with dependence on or abuse of both alcohol and illicit drugs 3.8 million were dependent on or abused drugs but not alcohol “a chronic, often relapsing brain disease that causes compulsive drug seeking and use despite harmful consequences to the individual that is addicted and those around them” (NIDA Info Facts 9/2007)

3. Stages of Addiction • 1. Acute reinforcement/social drug taking/Impulsive use • 2. Escalating/Compulsive use (e.g. binge drinking) • 3. Dependence: Use of a substance despite having clinically significant substance related problems. Discontinuation of the drug causes withdrawal symptoms and the person compulsively takes the drug. Physiological tolerance to the drug can develop • 4. Withdrawal: abrupt discontinuation or reduction in the use of a substance • 5. Protracted Abstinence • Relapse to the compulsive stage (craving) • Withdrawal symptoms are one of the causes of compulsive drug-taking behavior and short-term relapse. • 6. Recovery Neurobiology of Addiction 2006, p. 3

4. Drugs of Abuse Cocaine Indirect dopamine agonist via inhibition of DAT and promotion of DA release Amphetamine Indirect dopamine agonist via release of DA mediated via the Methamphetamine DA transporter Opioids Mu opioid agonist Tetrahydrocannabinol CB1 and CB2 agonist Ethanol Positive GABAergic modulator Nicotine nAchR agonist Long-term neurobiological and neuroanatomical changes. Main Effect of the drug (directly or indirectly) is upon the mesolimbic dopamine system of the brain with modulation of dopamine transmission and levels Nature Neuroscience, 2005, 8, 1445

5. Substance Abuse – Neurocircuitry of Reward System

6. Substance Abuse - Neurocircuitry European Neuropsychopharmacology (2007) 17, 377–393

7. Substance Abuse - Neurotransmitters Amphetamine transported Into neuron INC DA RELEASE GABA inhibits DA release Agonists inhibit GABA release Inc DA release

8. Chantix Goal: develop a compound that would blunt the craving and withdrawal of nicotine but without the abuse liability. First evidence: a. Nicotine replacement therapy (NRT) where the agonist nicotine is supplied via a transdermal patch can reduce craving and withdrawal. b. The nonselective nAchR antagonist mecamylamine reduces consumption. c. A combination of the two drugs (agonist + antagonist) achieved higher abstinence rates than NRT. Problem is: two drugs, two pharmacokinetic profiles. Second evidence: Mu opioid partial agonist buprenorphine reduces opioid dependence.  A partial agonist approach could be therapeutically valid

9. Chantix - Partial Agonist Theory When not smoking partial agonist can have a mild nicotine-like effect and relieve craving. Increasing the dose (abuse) causes no further effect. Need a drug with high binding affinity and brain penetration (Ceff – free brain levels) to compete with nicotine

10. Nicotinic ACh Receptors • CNS - 5 transmembrane proteins that are composed of  and/or  subunits. Each subunit contains 4 segments. Related in structure and sequence to GABA, glycine, 5HT3 receptors 2-10 subunit that binds acetylcholine 2-4 42 subunit predominates in the CNS – nicotine Ki = 0.95 nM 34antagonism addiction medication? (4)2 (4)3 agonist inc Na+ and K+ permeability (7)5 agonist inc Ca2+ permeability (agonist- cognition, ADHD) Function at presynaptic locations to regulate release of Glu, D, HT, Ach, and neuropeptides CHEM E-120

11. NAchRPharmacophore Model NAchR Muscarinic C=O in Ach serves as HBA

12. Animal Behavioral Models Impulsive use – Self-administration These methods (operant conditioning) study the positive reinforcing effects of drugs. Drugs that are self-administered by animals (rodent and non-human primates) tend to have a high abuse potential in humans. These studies are performed under various “schedules” to explore different aspects of reinforcement. Fixed ratio (FR) a fixed number of responses are required to obtain the reinforcer. Measurement of the reinforcing strength of a drug. Reinforcing: rate of responding on drug lever > control lever Progressive ratio (PR): the number of responses required are increased to the “break point” ~ greater the break point, greater reinforcing property of the drug.

13. Animal Behavioral Models Stimulus Properties of Drugs – Drug Discrimination These methods (operant conditioning) study the ability of an animal to discriminate (tell the difference) between drug and saline. Animal is first trained to associate a reward (food) with a correct lever press FR20 – when animal presses lever A drug is injected and after 20 presses food is delivered. After training when an animal is given a dose of drug it will chose the drug reinforced lever to be given food. If the animal is given a different drug and presses the drug reinforced lever then the animal is said to “generalize” to the new drug. The animal perceives the 2 drugs as being the same.

14. Discovery Phase “displace nicotine from its neuronal binding site and reduce the subjective experience of nicotine administration by simultaneously attenuating the dopaminergic response to nicotine” Examined the biological properties of known nicotinic drugs in: 1. drug discrimination 2. self-administration 3. ex vivo dopamine release – administer drug to animal, sacrifice and measure DA and/or metabolite levels in appropriate levels of brain. Cytisine – Ki = 0.17 nM at α4β2 but 56% of nicotine response Eastern European plant derived natural product Initial cost $30,000/kg – Anticipated 13-18 kg/acre (43,560 ft2) for $150/kg. Able to get locally 5.5 gm of pure material from 64 kg plant material

15. Discovery Phase Cytisine physical properties: very hydrophilic with logP = 0.01 and logD7.4 = -0.2 (measuring the P of salt) brain-to-plasma (B/P) ratio = 0.1 CSF-to-free-plasma ratio = 0.27 mw = 190 tPSA = 32.34 What is easily chemically modified? modify N – decrease in binding affinity modify ring EC50 = 95 nM vs 9 μM (cytisine) log D = 0.35 B/P = 1.4 partial agonist with ED50 = 0.032 mg/kg antagonist with ED50 = 0.179 mg/kg substituted for nicotine inhibited nicotine self-administration Genetic toxicity (Ames Test?)

16. Discovery Phase cation center Work off of 3-point pharmacophore polarizing group HBA synthesis of cytisine w/o the polarizable N and HBA C=O, prepared 100 compds/18 months Is HBA C=O important? Some other electronic effect more important?

17. Discovery Phase Explored other heterocycles but none proved useful. (Figure 8) However: from morphine literature Brilliant!!!! “Clearly the change in N position in proceeding from 52 to 53 manifests itself by an almost total loss of anti-nociceptive activity and a marked increase in toxicity” Nicotine and cytisine are toxic – compds 50 to 53 structurally similar to cytisine Could 53 bind to 42 ?????

18. Lead Optimization Ki 42 = 0.17 nM 34 nM 20 nM MOR > 2 μM % response of nicotine = 56% 0 (antagonist)

19. Lead Optimization SAR to date lead them to rethink role of H-bonding in binding of the compounds to α4β2. receptor π-electron – sp2 drug interaction Do not need the C=O, go to heteroaromatic ring systems containing heteroatoms

20. Development of varenicline (var en' ikleen)

21. Development of the Drug agonist partial agonist antagonist of nicotine

22. Screening Strategy

23. Screening Strategy

24. Chantix log P = 1.1 pKa = 9.9 logD7.4 = -0.28 mw=211 B/P (rat) = 3.5 <20% plasma protein binding – freely availiable 90% of drug excreted unmetabolized no CYP450 interaction t1/2 = 24 hours steady-state levels achieved in 4 days Phase 2 – 1 mg once per day (QD) 0.5 mg twice per day (BID) 1 mg BID best 1.0 mg twice per day (BID) Phase 3 – after 12 week period 44% 4-week abstinence (30% Bupropion, 18% placebo) after 1 year 22.4% 15.4% 9.3%

25. Chantix Some people have had changes in behavior, hostility, agitation, depressed mood, and suicidal thoughts (thinking about harming or killing oneself or planning or trying to do so) while taking varenicline. The role of varenicline in causing these mood changes is unclear since people who quit smoking with or without medication may experience changes in their mental health due to nicotine withdrawal. However, some of these symptoms occurred in people who were taking varenicline and continued to smoke. Some people had these symptoms when they began taking varenicline, and others developed them after several weeks of treatment or after stopping varenicline. These symptoms have occurred in people without a history of mental illness and have worsened in people who already had a mental illness. Tell your doctor if you have or have ever had depression, bipolar disorder (mood that changes from depressed to abnormally excited), schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions), or other mental illnesses. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000351/