Chapter 11 Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission R ICHARD A. GLENNON AND MAŁGORZATA DUKAT Drugs Covered in This Chapter* Antiemetic drugs (5-HT3 receptor • Rizatriptan • Imipramine antagonists) • Sumatriptan • Olanzapine • Alosetron • Zolmitriptan • Propranolol • Dolasetron Drug for the treatment of • Quetiapine • Granisetron irritable bowel syndrome (5-HT4 • Risperidone • Ondansetron agonists) • Tranylcypromine • Palonosetron • Tegaserod • Trazodone • Tropisetron Drugs for the treatment of • Ziprasidone Drugs for the treatment of neuropsychiatric disorders • Zotepine migraine (5-HT1D/1F receptor agonists) • Buspirone Hallucinogenic agents • Almotriptan • Citalopram • Lysergic acid diethylamide • Eletriptan • Clozapine • 2,5-dimethyl-4-bromoamphetamine • Frovatriptan • Desipramine • 2,5-dimethoxy-4-iodoamphetamine • Naratriptan • Fluoxetine Abbreviations cAMP, cyclic adenosine IBS-C, irritable bowel syndrome with nM, nanomoles/L monophosphate constipation MT, melatonin CNS, central nervous system IBS-D, irritable bowel syndrome with MTR, melatonin receptor 5-CT, 5-carboxamidotryptamine diarrhea NET, norepinephrine reuptake transporter DOB, 2,5-dimethyl-4-bromoamphetamine LCAP, long-chain arylpiperazine 8-OH DPAT, 8-hydroxy-2-(di-n- DOI, 2,5-dimethoxy-4-iodoamphetamine L-DOPA, L-dihydroxyphenylalanine propylamino)tetralin EMDT, 2-ethyl-5-methoxy-N,N- LSD, lysergic acid diethylamide PMDT, 2-phenyl-5-methoxy-N,N- dimethyltryptamine MAO, monomaine oxidase dimethyltryptamine GABA, g-aminobutyric acid MAOI, monoamine oxidase inhibitor SAFIR, structure–affinity relationship 5-HT, serotonin mCPBG, m-chlorophenylbiguanide SAR, structure–activity relationship 5-HTP, 5-hydroxytryptophan mCPG, m-chlorophenylguanidine SERT, serotonin transporter IBS, irritable bowel syndrome mCPP, m-chlorophenylpiperazine SSRI, selective serotonin reuptake inhibitor *Drugs available outside the U.S. are shown in italics. 365 LLemke_Chap11.inddemke_Chap11.indd 336565 112/9/20112/9/2011 22:23:14:23:14 AAMM 366 PART II / DRUG RECEPTORS AFFECTING NEUROTRANSMISSION AND ENZYMES AS CATALYTIC RECEPTORS SCENARIO Jill T. Johnson, PharmD, BCPS MB is a 34-year-old woman with migraines. She experiences pho- aura. After using sumatriptan for several months, taking it rou- tophobia and severe headaches with nausea and vision changes tinely up to 300 mg per day for 15 days of the month, she real- about twice per month. Recently she was prescribed sumatriptan ized it was not working as well as it had been. to take as abortive therapy once she begins to feel the migraine SEROTONIN United States, the substance was called serotonin, whereas in Italy, it was termed enteramine. Its total Serotonin could be considered the “baby boomer” of synthesis in the early 1950s confirmed that both sub- neurotransmitters: It was fi rst identifi ed in the late stances were the same structure: 5-hydroxytryptamine 1940s, its adolescent years were troubled, it made the (5-HT). Serotonin (5-HT) was later detected in numer- drug scene in the 1960s, and it nearly died of an over- ous plant and animal species, and in the mid-1950s, dose in the early 1970s. It could be considered the it was identified in the central nervous system (CNS) original “sex, drugs, and rock-and-roll” receptor (as will of animals. A neurotransmitter role was proposed. be described below [see also Chapter 19], serotonin 5-HT was implicated in a variety of central and periph- receptors have been implicated in sexual behavior, eral physiologic actions. It seemed to be involved in drug abuse [especially that involving classical halluci- vasoconstriction and vasodilation, regulation of body nogens], and the perception of sound)—but, it does temperature, sleep, and hormonal regulation, and much more. early evidence suggested that it could be involved in At one time, it was remarked that “serotonin doesn’t depression. The structural similarity between 5-HT do anything” (1). On reaching its middle years, sero- tonin matured and became an important topic of study, a household name, and more complicated than ever. Serotonin has been associated with, among TABLE 11.1 Some Indications and Treatment Claims other things, anxiety, depression, schizophrenia, drug for Novel Serotonergic Agents in the abuse, sleep, dreaming, hallucinogenic activity, head- Patent Literature ache, cardiovascular disorders, sexual behavior, and appetite control. Television ads now routinely refer to Aggression Esophagitis Obsessive-compulsive serotonin and serotonin receptor antagonists. This, disorders subsequently, prompted the comment that “it almost Alcoholism Gastric motility Pain appears that serotonin is involved in everything” (1). A review of the current patent literature provides Alzheimer’s disease Head injury Panic disorders an indication of some of the claims being made for serotonergic agents (Table 11.1). Tens of thousands Amnesia Headache Parkinson’s disease of papers have been published on serotonin. Much Anorexia Hypertension Psychosis is known—but an incredible amount remains to be learned. Bulimia Impotence Raynaud’s disease Cardiac failure Irritable bowel Schizophrenia N O syndrome OH Cardiovascular Ischemia Sedation H NH2 N disorders CH3 Cerebrovascular Migraine Sexual dysfunction N N disorders H H Cognition disorders Movement Sleep disorders Serotonin (5-HT) (+)-Lysergic acid diethylamide (LSD) Depression Nausea Substance abuse Drug abuse Neurodegenerative Substance dependence A hormonal substance was independently identi- disease fied in the late 1940s by two groups of investigators, Emesis Obesity Thromboembolism one in the United States and the other in Italy. In the LLemke_Chap11.inddemke_Chap11.indd 336666 112/9/20112/9/2011 22:23:15:23:15 AAMM CHAPTER 11 / SEROTONIN RECEPTORS AND DRUGS AFFECTING SEROTONERGIC NEUROTRANSMISSION 367 CLINICAL SIGNIFICANCE Discovery of the different types Unfortunately, they also may cause coronary vasoconstric- of serotonin receptors during tion, making them contraindicated in patients with underlying the past few years has created coronary artery disease. Antagonists of the 5-HT3 receptor, the potential to target these recep- ondansetron, and granisetron, work to lessen emesis in che- tors. Altering the chemical structures may motherapy-induced and radiation-associated emesis as well as improve tolerability, reduce the risk of side effects, improve postoperative nausea and vomiting. A variety of drugs work to efficacy, enhance compliance, or simply provide an alternative inhibit selective serotonin reuptake without acting on any spe- drug should another in the class fail to provide relief for a given cific serotonin receptor. Drugs such as fluoxetine, paroxetine, patient. sertraline, and fluvoxamine have been effective in the treatment The clinical effects of serotonin receptors are multifaceted. At of depression, obsessive-compulsive disorder, and panic disorder this time, only a few of the identified receptors have drugs that with varying degrees of side effects like weight gain, weight loss, are currently marketed for use in humans. Buspirone stimulates and drowsiness. the 5-HT1A receptor to cause antianxiety effects. The 5-HT1D Jill T. Johnson, Pharm.D., BCPS agonists, or the “triptans,” vary by side chains on essentially the Associate Professor same core structure to create compounds with different affinities Department of Pharmacy Practice for the 5-HT1D receptors and, likely, for other serotonin recep- College of Pharmacy tors as well. The varying affinities of each triptan for receptors University of Arkansas for Medical Science change the profiles of their effectiveness and adverse or compli- Little Rock, AR mentary effects. As a rule, the triptans work to treat migraine headaches by causing vasoconstriction. and the then recently discovered hallucinogenic agent Serotonin Biosynthesis, Catabolism, and Function (+)-lysergic acid diethylamide (LSD) intrigued investi- as Targets for Drug Manipulation gators. The observation led to speculation that 5-HT 5-HT is biosynthesized from its dietary precursor l-trypto- could be involved in the mechanism of action of this phan (5) (Fig. 11.1). Serotonergic neurons contain trypto- psychoactive substances and could also have a role in phan hydroxylase (l-tryptophan-5-monooxygenase) that certain mental disorders. LSD was shown to behave as converts tryptophan to 5-hydroxytryptophan (5-HTP), in a potent 5-HT receptor agonist in certain peripheral what is the rate-limiting step in 5-HT biosynthesis, and aro- receptor assays and as a potent antagonist in others. matic l-amino acid decarboxylase (a nonselective decar- The late 1960s and early 1970s, however, witnessed a boxylase previously called 5-HTP decarboxylase) that decline in 5-HT research as the result of three factors: decarboxylates 5-HTP to 5-HT. This latter enzyme is also 1) sophisticated experimental techniques were still responsible for the conversion of l-dihydroxyphenylala- lacking for the investigation of the central actions of nine (l-DOPA) to dopamine (see Chapter 13). The major 5-HT; 2) apart from ergolines (LSD-related agents), route of metabolism of 5-HT is oxidative deamination only a few potent 5-HT agonists or antagonists had by monoamine oxidase (MAO; specifi cally, by MAO-A) been developed; and 3) it was becoming increasingly to the unstable 5-hydroxyindole-3-acetaldehyde, which is difficult to understand how a single putative neu- either reduced to 5-hydroxytryptophol (∼15%) or to the rotransmitter substance could be involved in so many oxidized