Medicinal Chemistry 5210 - Fall 2006 - Davis Section.

1. Medicinal Chemistry 5210 - Fall 2006 - Davis Section. • http://www.pharmacy.utah.edu/medchem/faculty/davis/mdch5210.html • darrell.davis@hsc.utah.edu - Office: BPRB 295E - Phone: 581-7006 • Reading List (Foye’s Principles of Medicinal Chemistry, Fifth Edition) • 1- CNS Stimulants (3 lectures - Foye Ch. 12,18) • 2- Neuroleptic Antipsychotics (2 lectures - Foye Ch. 17) • 3-Opioid Analgesics (3 lectures - Foye Ch. 19) • Exam () • 4- Anticonvulsants (2 lectures - Foye Ch. 16) • 5- Antihistamines (2 lectures - Foye Ch. 33) • 6- General Anesthetics (1 lecture - Foye Ch. 14) • 7-Local Anesthetics (1 lecture - Foye Ch. 13) • Exam () • Old Exams - Available on the Web Page. Lectures - PPT files available on the Web Page.

2. CNS StimulantsTherapeutic Treatment for: Depression, Narcolepsy, Obesity Analeptic - A CNS stimulant that causes muscle contraction and perhaps also convulsions. Particularly a term used to describe compounds that cause contraction and rigidity of the muscles of respiration. Strychnine is the most commonly recognized analeptic although it has relatively low potency. Mechanisms of Action for CNS Stimulants: Block neurotransmitter reuptake (Most reuptake inhibitors affect either NE or 5HT) Tricyclic antidepressants Cocaine Selective Serotonin reuptake inhibitors 2. Promote Neurotransmitter Release Phenylethylamines and related compounds. Amphetamine, Methylphenidate. 3. Block Metabolism - MAO inhibitors

3. Non-Therapeutic CNS stimulants(all seizure inducers) Strychnine - Inhibits glycine receptors Picrotoxin - Acts on the chloride ion channel associated with GABA receptors. Bemigride - Barbiturate Antagonist Pentylene tetrazole - Na+/K+ channel blocker? Increases cholinergic activity.

4. Xanthines (Caffeine, theophylline, theobromine) • Mechanism(s) of action: • Inhibition of cAMP phosphodiesterase • Competitive inhibitor of adenosine • Promote NE release • Promote intracellular Ca+2 release The order of potency for CNS activity is Caffeine > Theophylline > Theobromine Theophylline is an important drug for maintenance treatment of asthma, but has some side effects as you might expect.

5. Phenylethylamines • Enhance neurotransmitter release • Block NT reuptake • Have direct agonist effects • MAO inhibition Phenylethylamines are used as anorectics, for narcolepsy, and ADHD. Not legitimate antidepressants. The SAR is relatively well-defined as we learned for the indirect acting NE agonists. The phenyl ring and the distance between the amine and the phenyl is fairly strict. For the phenidates, the SAR of methyl phenidate is optimal. Changes that affect the rate of methyl ester hydrolysis affect duration and potency. With the exception of anorexia, many of the CNS effect of phenylethylamines are thought to involve effects on dopamine release and reuptake. “Amphetamine induces dopamine efflux through a dopamine transporter channel” PNAS (2005) vol. 102 |3495-3500

6. Amphetamine Structures

7. Neuronal Synapse - NE Mechanism Goodman and Gilman, 9th Edition

8. Neuronal Synapse - 5HT Tryptophan Tryptophan LNAA 5-HT1A TPH 5-HTP AADC 5-HT Pre-synaptic 5-HIAA MAO 5-HT 5-HT1B SERT 5-HT2c 5-HT1A 5-HT2A 5-HT1B Post-synaptic

9. Halogen Substituted Phenylethylamines. “The Halogen Rule ™” Halogen substitutions provide for 5HT selectivity/specificity. The halogen rule, also applies to reuptake inhibitors.

10. A few thoughts on Anorectics. Regulation of food intake is a complicated process. Pretty much all of the major CNS neurotransmitter systems have been implicated. However, direct injection of serotonin reduces food intake, and fenfluramine requires an intact serotoninergic system for its anorectic effects. A problem is that reduction in food intake is usually accompanied by a feeling of hunger. Addressing this was the promotion of the theory that increasing serotonin levels while simultaneously increasing dopamine levels would be beneficial. Increased DA would reduce the feelings of hunger. Therefore Phentermine with Fenfluramine. Don’t quite understand how you reduce food intake, without diminishing hunger, but there you have it.

11. Fen-Phen Lawsuits - Many Ashcraft & Gerel LLP The Victims' Rights Law Firm Washington, D.C. Maryland (Baltimore Landover Rockville) Virginia FEN-PHEN DIET DRUG LITIGATION - FREQUENTLY ASKED QUESTIONS Introduction What should I do medically if I used these drugs? What is Fen-Phen? What is Redux? What Heart Valve Problems are caused by these drugs? What is Primary Pulmonary Hypertension? What types of Neurotoxicity are associated with these drugs? What can I do legally to protect myself?

12. Did Phen/Fen cause heart valve damage? Maybe - Was there long term damage? Clinical and Echocardiographic Follow-up of Patients Previously Treated With Dexfenfluramine or Phentermine/Fenfluramine Julius M. Gardin, MD; Neil J. Weissman, MD; Cyril Leung, MD; Julio A. Panza, MD; Daniel Fernicola, MD; Kelly D. Davis, MD; Ginger D. Constantine, MD; Cheryl L. Reid, MD JAMA. 2001;286:2011-2014. ABSTRACT Context Use of anorexigen therapy is associated with valvular abnormalities, although there is limited information on long-term changes in valvular regurgitation following discontinuation of these agents. Objective To evaluate changes in valvular regurgitation, valve morphology, and clinical parameters 1 year after an initial echocardiogram in patients previously treated with dexfenfluramine or phentermine/fenfluramine and in untreated controls. Design and Setting A reader-blinded, multicenter, echocardiographic and clinical 1-year follow-up study at 25 outpatient clinical sites. Patients A total of 1142 obese patients (1466 participated in the initial study) who had follow-up echocardiogram; all but 4 had a follow-up medical history and physical examination. Follow-up time from discontinuation of drug to follow-up echocardiogram for 371 dexfenfluramine patients was 17.5 months (range, 13-26 months) and for 340 phentermine/fenfluramine patients was 18.7 months (range, 13-26 months) after discontinuation of drug therapy. Main Outcome Measure Change in grade of valvular regurgitation and valve morphology and mobility. Results Echocardiographic changes in aortic regurgitation were observed in 8 controls (7 [1.7%] had decreases; 1 [0.2%] had an increase); 29 dexfenfluramine patients (23 [6.4%] had decreases; 6 [1.7%] had increases; P<.001 vs controls); and 15 phentermine/fenfluramine patients (4.5% all decreases; P = .03 vs controls). No statistically significant differences were observed when treated patients were compared with controls for changes in medical history, physical findings, mitral regurgitation, aortic or mitral leaflet mobility or thickness, pulmonary artery systolic pressure, ejection fraction, valve surgery, or cardiovascular events. Conclusion: Progression of valvular abnormalities is unlikely in patients 1 year after an initial echocardiogram and 13 to 26 months after discontinuation of dexfenfluramine and phentermine/fenfluramine

13. The Good -old Days of Antidepressants Dexamyl: Dextroamphetamine + amobarbital A better one was “Desbutal” : methamphetamine and pentobarbital

14. Monamine Oxidase (MAO) Inhibitors Two MAOs, MAO-A and MAO-B. Selective MAO-B inhibitors increase levels of dopamine in the brain, therefore may be useful for Parkinson’s disease. MAO inhibitors are sometimes used as antidepressants, when patients don’t respond to the tricyclics. There are “atypical” cases of depression that respond to MAO inhibitors, but not to tricyclics or electroshock therapy. Mechanism of Action. Elevate levels of most monamine neurotransmitters. However, the antidepressant effects take 2-4 weeks to manifest. This suggests that adaptive changes in receptors, or the balance of NT levels are responsible for the antidepressant effects. For instance -adrenergic receptors appear to be down-regulated. Also, increased DA levels may lead to increased intracellular NE levels over and above the increases as a direct result of MAO inhibition. Complicated stuff.

15. MAO SAR MAO SAR Primary sites of binding are the side chain amine and the aromatic group. Electron withdrawing groups increase potency. For the irreversible compounds, a reactive hydrazine, cyclopropyl, or acetylene (alkynyl) group is present. RIMAs (reversible inhibitors of MAO) don’t have this. The enzyme is stereoselective as indicated by the preference (3-fold) of the trans vs. cis tranylcypromine (Parnate) compounds. There is that rigid analog thing again. The two enantiomers of amphetamine also show different levels of inhibition of MAO.

16. Tricyclic Antidepressants The “amine theory of depression.” Drugs that increase the levels of amine neurotransmitters are potential antidepressants. Does depression arise due to abnormally low levels of amine neurotransmitters? Most antidepressants, especially the first generation drugs increase the levels of amines. The effect on amine NT levels is immediate. However, the antidepressant effects take 1-2 weeks to become apparent. Therefore focus has shifted somewhat to adaptive effects in receptor systems, primarily the -adrenergic receptors and their associated cAMP second messengers systems, but pretty much the entire list of adrenergic, serotoninergic, DA, GABA, etc. systems. Partially out of recognition that these are often intertwined. cAMP production is stimulated, then an adaptive decrease in adrenergic receptor sites occurs, ultimately decrease the levels of adenylate cyclase and cAMP.

17. Blier, P. Eur Neuropsychopharmacol. 2003 Mar;13(2):57-66 Abstract: Depressionis a serious and burdensome illness. Although selective serotonin reuptake inhibitors (SSRIs) have improved safety and tolerability of antidepressant treatment efficacy, the delay in the onset of action have not been improved. There is evidence to suggest that the delay in onset of therapeutic activity is a function of the drugs, rather than the disease. This suggests that research into the biological characteristics of depression and its treatments may yield faster-acting antidepressants. Emerging evidence from clinical studies with mirtazapine, venlafaxine and SSRI augmentation with pindolol suggests that these treatments may relieve antidepressant symptoms more rapidly than SSRIs. The putative mechanism of action of faster-acting antidepressant strategies presented here purports that conventional antidepressants acutely increase the availability of serotonin (5-hydroxytryptamine, 5-HT) or noradrenaline (NA), preferentially at their cell body level, which triggers negative feedback mechanisms. After continued stimulation, these feedback mechanisms become desensitised and the enhanced 5-HT availability is able to enhance 5-HT and/or NA neurotransmission. Putative fast-onset antidepressants, on the other hand, may uncouple such feedback control mechanisms and enhance 5-HT and/or NA neurotransmission more rapidly. Further studies are required to characterise in detail the interactions between NA and 5-HT systems and to definitively establish the early onset of candidate antidepressants such as mirtazapine, venlafaxine and pindolol augmentation. The pharmacology of putative early-onset antidepressant strategies

18. Tricyclic Antidepressant SAR- The first generation compounds have a central, tricyclic ring stucture. The three-dimensional structure is thought to be important, with a puckered, non-planar structure distinguishing antidepressants from related compounds such as the antipsychotic, post-synaptic dopamine antagonists. Short amine side chains are important for the older and newer antipsychotics.. Monomethyl amines are more potent than dimethylamines as shown for imipramine and desipramine. Ring substitutions have little effect on NE and dopamine activity, Halogen substitution does not increase activity and is not necessary for DA tricyclic activity as seen for the closely related DA antagonists. The Halogen Rule, Again. Halogen substituted compounds are generally more selective for 5HT receptors. Although the selective serotonin compounds are often not tricyclic, they can adopt a similar conformation and do show cross-reactivity with DA and NE sites.

19. Representative Tricyclic Structures. (The important ones)

20. IC-50’s of 5-HT/NE/DA Reuptake Inhibitors Zoloft Paxil Lower IC50 means greater receptor affinity High NE/5-HT - more selective for 5-HT

21. Reuptake Inhibitor Structures

22. Miscellaneous CNS Stimulants - Hallucinogens Mechanism of Action -(The usual) Phenylethylamines promote NT release and inhibit MAO. The hallucinogenic effects probably are due to 5HT activity. The simple indole alkaloids probably have similar actions, though may have specificity for 5HT sites. More complex indoles have high affinity for 5HT receptors and have full or partial agonist activity.

23. Aldous Huxley Had the Answer

24. Hallucinogen Structures Mescaline ~300 mg dose LSD ~3000 MUs

25. SAR for Phenylethylamine Hallucinogens, Stimulants

26. Phenylisopropylamines

27. Attention Deficit Hyperactive Disorder – ADHD Treatments – The most widely used is Methylphenidate, followed by dextroamphetamine, tricyclic antidepressants. What is the “cause”? ADHD has a strong inheritance link. Children with ADHD often have siblings with the disorder, other relatives, and appear to inherited a predisposition for the disorder.

28. Dopamine Receptors and ADHD The dopamine D4 receptor, DRD4, gene seems to be linked with inheritance patterns for ADHD. The DRD3 and DRD5 genes show no linkage. That is, heritance patterns of these genes and ADHD are not correlated. Other possible neuronal systems that play a role in ADHD include serotonin HTR2A and SNAP-25 which is a protein involved in vesicle fusion. Mice with SNAP-25 mutants are spontaneously hyperactive, but respond to dextroamphetamine. Mol. Psychiatry (2000) 5, 405 (snap-25) Mol Psychiatry (2000) 5, 537 (HTR2A) J Clin Psychiatry. 2006;67 Suppl 8:13-20. Candidate gene studies of attention-deficit/hyperactivity disorder

29. Do we understand what causes ADHD? What does this mean? Methylphenidate (Ritalin) treatment is controversial Dextroamphetamine (Adderall) treatment is probably more controversial Clinical Trials (Evid. Rep. Tech. Asses. (1999) 11, 1-341) indicate that methylphenidate and dextroamphetamine are probably the most effective treatments, better than tricyclic antidepressants, although desipramine may be beneficial. Successful ADHD treatment with MPH is consistent with the D4 receptor gene alleles showing co-inheritance with ADHD. Previous DAT1, DA transporter linkage is not supported, but serotonin 2A receptors do show linkage. Finally: There seem to be an emerging consensus that ADHD has a genetic component, there are specific receptors involved, the disorder responds to stimulants, and this response is consistent with the receptors. The challenge would then be to correctly diagnose the disorder, and to also develop new drugs that are more selective.

30. Reuptake Inhibitors - Again Can you see the SAR (structural) similarity between fluoxetine, paroxetine, sertraline,and atomoxetine?

31. Newer Antidepressants – Additional Mechanisms of Action Conventional antidepressants acutely increase the availability of NA and 5HT, triggering negative feedback mechanisms. This feedback becomes desensitized with time and the enhanced availability of 5HT, primarily, enhances 5HT neurotransmission. Fast-onset antidepressants, in contrast, uncouple the feedback (inhibit 2 autoreceptors for example) and have a more immediate effect.

32. Some of the New(er) Guys • Mirtazapine (Remeron) Presynaptic 2-antagonist – Acts to increase the levels of both NA and 5HT. Additionally blocks post-synaptic 5HT2 and 5HT3 receptors, without affecting 5HT1. Benefits are decreased side effects and more immediate antidepressant action. • Trimipramine (Surmontil) Supposedly is both an antipsychotic like clozapine and an antidepressant. Despite the “tricyclic” structure, it does not have significant reuptake inhibition activity. Mechanism is sketchy • Nefazodone (Serzone)5HT2A (serotonin) antagonistand modest NA and 5HT reuptakeinhibitor (SARI). Structurally unrelated to other antidepressants, but chemical similar to butyrophenone antipsychotics. • Trazodone (Desyrel) May also be a SARI • Atomoxetine (Strattera) SNRI – Serotonin/Norepinephrine reuptake inhibitor. Newer treatment for ADHD. • Venlafaxine (Effexor)SNRI • Bupropion (Wellbutrin)NDRI - Norepinephrine/Dopamine

33. Mechanisms of Antidepressants: Tryptophan Tryptophan LNAA 5-HT1A TPH 5-HTP AADC 5-HT Pre-synaptic 5-HIAA MAO 5-HT 5-HT1B SERT 5-HT2c 5-HT1A 5-HT2A 5-HT1B Post-synaptic Mechanisms of Antidepressants: NA & DA RI (NDRI) Serotonin/NA RI (SNRI) 5HT2A antagonist, NA & 5HT RI (SARI). 2 antagonist, NA & 5HT RI

34. Venlafaxine/Bupropion Structures Venlafaxine (Effexor) SNRI Bupropion (Wellbutrin) NDRI Norepinephrine/Dopamine These are structurally unrelated to other tricyclics and perhaps are Mechanistically distinct.