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CHEM E-120Harvard University Extension School

Stimulants

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ADHD

Attention Deficit Hyperactivity Disorder

Principle Characteristics:

Excessive HyperactivityExcessive Impulsivity Excessive Inattention

Arises before age 7, thought to affect up to 12% of school-age children and perhapsas many adults.

No pathological diagnostic tool. Diagnosis based on the recognition of patterns of behavior for children. Lack of reliable diagnosis for adults

Comprehensive Medicinal Chemistry II, Chapter 6.05

Impairment in social, academic, or occupational functioning

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ADHD - GeneticMost likely a polygenic disease – some reported linkages

DAT1 – dopamine transporterDRD2 – Dopamine D2

DRD4 – Dopamine D4

DRD5 - Dopamine D5

DBH – dopa-β-hydroxlaseα4 subunit of acetylcholine nicotinic receptorsSNAP-25 – synaptosomal-associated protein of 25 kDa

increased transmission of Ddel allele 1 (Ireland)increased transmission of Ddel allele 2 (Canada)

SNAP-25 : presynaptic plasma membrane protein involved in synaptic transmission

Comprehensive Medicinal Chemistry II, Chapter 6.05, p120

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ADHD - ComorbidityLearning Disabilities

20 - 30% of children with ADHD have a specific learning disabilitydifficulty in understanding certain sounds or wordsdifficulty in expressing oneself in wordsdyslexia – a type of reading disorderspelling, writing, arithmetic disorders

Tourette Syndrome

Oppositional Defiant Disorder (ODD)up to 50% of children with ADHD (mainly boys)Defiant, stubborn, noncompliant, outbursts of temper, argumentative

Conduct Disorder (CD)20 - 40% may develop CD – violent, aggressive, more serious than ODD

Anxiety, Depression, Bipolar Disorder

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ADHD – Medication DevelopmentAnimal Models

All involve the overt expression of phenotypic trait of ADHD – often dependent upon thebehaviorial testing method

Spontaneously Hypertensive Rat (SHR)Strain of Wistar Kyoto (WKY) rats discovered in Japan

Dopamine transporter (DAT) knockout mouse300 fold decrease in the rate of clearance of extracellular dopamine

Synaptosome-associated protein of 25 kDa (SNAP-25, coloboma mutant)2-4 fold increase in hyperactivity (spontaneous locomoter activity) when tested innovel environment.

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Neurobiology

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ADHD - Medication

www.nimh.nih.gov/health/publications/adhd-listing.shtml

Trade Name Generic Name Approved Age (years)

Adderall amphetamine ≥ 3

Concerta Methylphenidate (long acting) ≥ 6

Metadate ER Methylphenidate (extended release) ≥ 6

Metadate CD Methylphenidate (extended release) ≥ 6

Ritalin Methylphenidate ≥ 6

Ritalin SR Methylphenidate (extended release) ≥ 6

Ritalin LA Methylphenidate (long acting) ≥ 6

Straterra Atomoxetine

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Dopamine Hypothesis

Hypofunctional dopaminergic system may be a fundamental mechanism of ADHD.

Stimulant medication is an effective therapeutic approach for ADHD. Increases dopamine levels

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Methylphenidate - Ritalin

hypertensive action

JMC 1998, 41, 591

DAT IC50 = 171 nM 1468 nMNET IC50 = 128 nM 876 nM

Clin Pharmacokinet 1999, 37, 457-470

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Methylphenidateextracellular monoamine levels in the striatum of freely-moving SH rats

Oral methylphenidate takes ~ 2.5 hr to reach peak brain concentrationIV methylphenidate produces effects similar to IV cocainelong peak brain concentration reduces reward-seeking behavior

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Methylphenidate

Am J Psychiatry 155:10, October 1998

PET to measure displacement of [11C]cocaine in human subjects

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Methylphenidate Binding in Brain

Raclopride D2 ligand that competeswith dopamine

Image shows that the amount ofraclopride present is reduced whenmethylphenidate is on board

the reduced levels of raclopride are dueto increased levels of dopamine induced by MP displacing bound raclopride from D2

13J. Org. Chem. 1998, 63, 9628-9629

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Asymmetric Synthesis - Novartis

J. Organic Chemistry 1999, 64, 1750

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Atomoxetine (Strattera)

selective NET reuptake inhibitor

NET Ki = 4.5 nMDAT Ki = 152 nMSERT Ki = 657 nM

Pediatric Drugs 2009; 11 (3): 203.226CNS Drugs. 2010 Jan 1;24(1):85-8

Does not appear to be as effective as methylphenidate

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Atomoxetine

PFC

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Lily Manufacturing Route

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Modafinil (Provigil)

DAT IC50 nM NET IC50 nM SERT IC50 nM

Modafinil 6390 35,600 >500,000

Methylphenidate 25 26

Bupropion 1088

JPET 2006, 319 561–569

Complex effects on dopamine, serotonin, norepinephrine, Glutamate, and GABA levelsNeuropsychopharmacology 2007, 1-26

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Modafinil (Provigil)

Bioorganic & Medicinal Chemistry 16 (2008) 9904–9910

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Modafinil (Provigil)Psychiatry Res. 2009 Aug 15;168(3):234-7A randomized, double-blind and placebo-controlled trial of modafinil in children and adolescents with attention deficit and hyperactivity disorder.All study subjects were randomly assigned to receive treatment with modafinil in a film-coated tablet, 200-300 mg/day, depending on weight (200 mg/day for <30 kg and 300 mg/day for >30 kg) (group 1) or placebo (group 2) for a 6-week double-blind, randomized clinical trial. The principal outcome measure was the Teacher and Parent ADHD Rating Scale-IV. Patients were assessed by a psychiatrist at baseline, 14, 28 and 42 days after the medication started. At 6 weeks, modafinil produced a significantly better outcome on the Parent and Teacher Rating Scale scores than placebo. Decreased appetite was observed more often in the modafinil group. The results of this study indicate that modafinil significantly improved symptoms of ADHD, was well tolerated, and may open a new window in the treatment of children with ADHD

J Pediatr. 2008 Mar;152(3):394-9.Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescentsThe patients were boys and girls age 6 to 17 years. ADHD subtype diagnoses (ie, inattentive, hyperactive-impulsive, combined) were based on criteria published in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Patients received modafinil (170 to 425 mg) or placebo once daily for 7 to 9 weeks. Efficacy assessment used the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions, Clinical Global Impression of Improvement scale (CGI-I), and Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). RESULTS: A total of 638 patients received modafinil (n = 423) or placebo (n = 215). The inattentive, hyperactive-impulsive, and combined subtypes included 187 (30%), 27 (4%), and 403 (65%) patients, respectively. Modafinil (vs placebo) significantly improved mean total scores for the ADHD-RS-IV School and Home Versions for the inattentive (change from baseline: School, modafinil, -15.7, placebo, -7.1; Home, modafinil, -13.8, placebo, -5.9) and combined subtypes (School, -16.5 vs -8.8; Home, -15.7 vs -7.6). Modafinil was associated with greater improvements on the CGI-I and improved CPRS-R:S subscale scores in inattentive and combined subtypes. CONCLUSIONS: Modafinil improved ADHD symptoms and behaviors in patients with the inattentive and combined subtypes as determined by teachers, investigators, and parents

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Substance Abuse Stimulants

Cocaine dependence or abuse in 2006 were 1.7 million.

The primary action of cocaine is binding to the dopamine transporter (DAT) and preventing reuptake of synaptic dopamine. Most drug strategies have focused on methods to reduce the effects of excess dopamine.

These include partial antagonists at dopamine receptors, D3 agonists, or indirect modulation by interaction with the opioid, serotonin, norepinephrine, and sigma receptor systems

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Medication Development Cocaine Abuse Modafinil: stimulant drug that is approved for the treatment of narcolepsy. Modafinil binds weakly to DAT (IC50 = 6.4 M) and NET (IC50 = 35.6 M) but not to SERT (IC50 > 500 M) and has been shown to occupy striatal DAT and thalamic NET sites in rhesus monkeys using positron emission tomography (PET) imaging. In a small-scale clinical trial, modafinil, at 200-400 mg/day, attenuated smoked cocaine self-administration in frequent users.

Tiagabine: GABA uptake inhibitor, 24 mg/day was shown to reduce cocaine taking behavior among methadone-stabilized cocaine abusers.

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Substance Abuse Stimulants

Methamphetamine abuse is particularly troublesome. Its incidence of use is similar to that of crack cocaine (700,000 users within the past month).

Methamphetamine acts intracellularly by binding to vesicular monoamine transporters (VMAT2) causing the release of dopamine (JPET 2006, 319, 237), activates trace amine-associated receptor 1 (TAAR1).

Neurotoxic resulting in reduction of D2 and DAT

cocaine elimination t1/2 = 1 hour, smoking produces 20-30 minute high meth elimination t1/2 = 12 hour, smoking produces a 2-24 hr high

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Meth Synthesis

List Of All Supplies

6-8 Regular Pint Size Mason Jars 2 Boxes Contact 12-hour time released tablets 2 Bottles of Heet 4 feet of surgical tubing 1 Gallon Muriatic Acid 1 Gallon of Coleman's Fuel 1 Gallon of Acetone 1 Pack of Coffee Filters 1 Electric Hotplate 4 Bottles Iodine Tincture 2% (Not Decolorized) 1 Bottles of Hydrogen peroxide 2 20-0z Coke Bottles (Plastic type, w/ Caps) 1 Can Red Devils Lye 4 Boxes Book Matches (Red/Brown Striker Pads) 1 Pyrodex Bowl 2 Razor Blades 1 digital scale that reads grams 1 gallons distilled water 1 Roll Aluminum foil tape 2 Coffee Cups

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Meth SynthesisGood Manufacturing Practice

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Meth SynthesisDilute Hydrochloric acid--> This may be purchased at the hardware store. It's sold as a brick and driveway cleaner. They call it muriatic acid. Sodium Hydroxide--> This, you probably already have. It's called "lye" at most places; it's drain cleaner. Ethyl Ether--> You'll probably have to make this. Don't worry, it's a breeze. Just go to your local K-mart or Auto parts store, and get a can of that "STARTING FLUID" it comes in a spray can. It's used for cold weather starting of gasoline engines."VICKS" nasal inhalers-->USE ONLY VICKS!! No other kind will work that I know of. These are at any drug store or grocery, etc.. You need 12 of em, but don't buy em' by the dozen, unless its winter time, then you can just say yer from some nursing home, and you're stockin up for the patients. Otherwise buy em' 2 at a time, if possible. Get a friend to help you.The druggists at the drug store usually will know what's goin on if you buy quantity.

PREPARING ETHER! (DO THIS FIRST) Take one of the small bottles and spray starter fluid in it till it looks half-full. Then fill the rest of the way with water, cap the bottle and shake for 5 minutes. Then, draw off the top layer with the eyedropper, and throw away the water layer. Repeat this until you have about 3 oz. of ether. Put the cap on it, and put it in the refrigerator if you can. (If you can't, don't worry about it) You'll use this in the procedure below.

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Medication Development for MethAripiprazole: D2 partial agonist, attenuates behavorial effects of d-amphetamine and is proposed to be of possible use for the treatment of stimulant abuse.

Lobeline has shown promise as a potential medication for treating methamphetamine abuse. This compound is fairly promiscuous acting as a mu opioid receptor antagonist (K i = 740 nM), a 42 and 7 nicotinic acetylcholine receptor agonist/antagonist (Ki = 10 – 20 nM), VMAT2 inhibitor (IC50 = 1 M), and a DAT inhibitor (Ki = 40 – 100 M).

Bupropion: DAT inhibitor, was tested for efficacy in increasing the weeks of abstinence in methamphetamine-dependent patients (n=151). Seventy-two patients were randomized to placebo and 79 to sustained-released bupropion 150 mg twice daily. It was found that bupropion was effective in increasing the number of weeks of abstinence in patients with a low-to-moderate methamphetamine dependence.