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The Serotonin-7 Receptor As a Novel Therapeutic Target

The Serotonin-7 Receptor As a Novel Therapeutic Target

The -7 Receptor as a Novel Therapeutic Target

Stephen M. Stahl, MD, PhD

Issue: Blockade of 5-HT7 receptors may be a novel therapeutic approach for achieving and memory-enhancing actions.

here are more than a dozen re- namely, the suprachiasmatic nucleus candidates for clinical testing as anti- Tceptor subtypes for serotonin of the hypothalamus; the hippocam- depressants as well. (5-hydroxytryptamine, 5-HT), but only pus, cortex, and thalamus; and also in Combining agents such as 2 of them are generally well known to the midbrain raphe nuclei, probably on or with SSRIs would be pre- clinical psychopharmacologists1: the GABA interneurons or on glutamate dicted to enhance 5-HT release as well 3,4,7 3–5,8 5-HT1A receptor, stimulation of which terminals. Numerous animal stud- as to have antidepressant properties. is linked to antidepressant and anxio- ies have demonstrated the role of 5-HT7 Given the recent positive results as lytic actions, and the 5-HT2A receptor, receptors in preclinical antidepressant an antidepressant for the melatonergic/ blockade of which is linked to the re- actions, learning, memory, sleep, and serotonergic agent , which duction of extrapyramidal side effects circadian rhythms.3–9 resets circadian rhythms,18 combining and other side effects of the second- novel 5-HT7 antagonists with melatonin 1,2 generation atypical . 5-HT7 Receptors as Novel agonism may also enhance the antide- Now comes the 5-HT7 receptor onto Therapeutic Targets pressant actions of 5-HT7 antagonists. 2–17 3,5,8,9 the scene, not just because of the Although no selective 5-HT7 com- In addition, preclinical studies sug­ development of specific compounds pounds are available for clinical use, gest the possibility that agents with po- allowing characterization of this re- numerous compounds are sufficiently tent 5-HT7 antagonism may improve 3,5,7–9 ceptor, but also because of the potent blockers of 5-HT7 receptors such cognition, so cognition in depression, discovery that several of the known an- that 5-HT7 antagonism could theoreti- , and other illnesses is a tidepressants and antipsychotics block cally contribute to their pharmacologic theoretically attractive clinical target, 10–17 5-HT7 receptors, and that this 5-HT7 actions (Table 1). In particular, sev- for 5-HT7 antagonists as well. antagonism may account in part for the eral of the compounds listed in Table therapeutic properties of these , 1 are effective , and in 10–17 Table 1. Agents With Potentially especially antidepressant actions. animal models, the antidepressant ef- a Clinically Relevant 5-HT7 Antagonism ficacy of is reversed in ani- 8 Second-Generation Atypical Antipsychotics Localization and Function of mals lacking 5-HT7 receptors, and the 5-HT7 Receptors serotonin release and antidepressant Asenapine Serotonin-7 receptors are postsyn- actions of selective serotonin reuptake aptic G protein–linked receptors that inhibitors (SSRIs) are enhanced by se- Lurasidone 3,5,8 may regulate serotonin-glutamate in- lective 5-HT7 antagonists. 3,4,7 teractions. They are distributed Three novel agents characterized in areas that explain their functions, as antipsychotics have 5-HT7 antago- nist properties among their most po- Brainstorms is a section of The Journal of tent pharmacologic actions (Figure 2,10,13,14 First-Generation Conventional Antipsychotics Clinical Psychiatry aimed at providing updates of 1), and 1 of these, lurasidone, novel concepts emerging from the neurosciences Cyamemazine that have relevance to the practicing psychiatrist. in late-stage clinical development as From the Neuroscience Education Institute an , is actually “5-HT7 in Carlsbad, California, and the Department of preferring,” with 5-HT7 antagonism its Psychiatry at the University of California San 13 Diego, and the Department of Psychiatry at the most potent property. Of these, ami- Antidepressants University of Cambridge, Cambridge, United sulpride (not available in the United Kingdom. 1,2,14 For reprint and financial disclosure States) is a proven antidepressant. information, go to www.psychiatrist.com/ Theoretically, because of their even brainstorms. greater potency for 5-HT7 antagonism, doi:10.4088/JCP.10bs06601gry aBased on data from references 10–17. © Copyright 2010 Physicians Postgraduate Press, Inc. lurasidone and asenapine are good

J Clin Psychiatry 71:11, November 2010 1414 Ta k e -Ho m e Po i n t s

◆◆ The 5-HT7 receptor is a novel serotonin receptor whose properties have recently been characterized. ◆◆ Serotonin-7 receptors are localized in cortex, hippocampus, hypothalamus, thalamus, and brainstem raphe nuclei, where they regulate mood, circadian rhythms, sleep, learning, and memory. ◆◆ Several known antipsychotics and antidepressants with multifunctional pharmacologic actions have been recently discovered also to block 5-HT7 receptors, and this mechanism could hypothetically be linked in part to their antidepressant actions.

Figure 1. Novel Multifunctional Drugs With the Most Potent 5-HT7 Antagonist Actions

5-HT 5-HT 5-HT

1A 1A H2 1B H α 1 1 α1 5-HT2A 5-HT2A α2A α2C α2B 5-HT2B Lurasidone Asenapine α2C Amisulpride 5-HT2C D1

5 5-HT D2 D2 6 D2 D 5-HT 7 D D 3 7 D 3 7 4 D4 3

5-HT 5-HT 5-HT Partial Agonist

Re f e r e n c e s

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