Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs (original) (raw)
Serotonin, which was known to be the principal vasoconstricting substance found in serum, was chemically identified as 5-hydroxytryptamine by Rapport and colleagues in 1948 (1). Although the effects of serotonin on smooth muscle and other peripheral organs were long appreciated, it wasn’t until its structural similarity to lysergic acid diethylamide (LSD) was noted that serotonin and its receptors were linked to neurotransmission (2). Distinct serotonin receptor subtypes were proposed in 1957 (3), with the 5-HT1 receptors having high affinity for serotonin and the 5-HT2 receptors having relatively low affinity for 5-HT. The so-called 5-HT1 and 5-HT2 receptors identified pharmacologically by Gaddum and colleagues (3) roughly correspond to what are now known as the 5-HT1 and 5-HT2 families of receptors (Figure 1).
Sites of action of 5-HT therapeutics. Shown in the middle is a table listing the major families of 5-HT receptors (viz. 5-HT1 to 5-HT7). As shown, the 5-HT1 family has five members (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F), while the 5-HT2 family — the topic of this review — has three: 5-HT2A, 5-HT2B, and 5-HT2C. Each member of the 5-HT2 family displays distinct brain and tissue distributions. The 5-HT2A receptor is enriched in pyramidal neurons in layer V of the cerebral cortex, where it mediates the actions of pimavanserin and other atypical antipsychotic drugs. The 5-HT2B receptor is enriched in interstitial cells of the heart valves, where it mediates the valvulopathic actions of certain drugs like fenfluramine. The 5-HT2C receptor is enriched in the hypothalamus, among other areas, particularly in nuclei engaged in regulating feeding behavior, where it mediates the actions of the appetite suppressant lorcaserin.
With the development of radioligand-binding technology, multiple distinct serotonin receptors were identified based principally on their differential radioligand-binding properties. Following the cloning of the β-adrenergic receptor (4), 5-HT1A (5), the first so-called orphan GPCR, was cloned by Brian Kobilka in collaboration with Marc Caron and others (6, 7). In rapid succession, the large family of G protein–coupled serotonin receptors we now appreciate were identified by molecular cloning technology and characterized by pharmacological and biochemical studies (8, 9), including 5-HT1B/1D (10) and 5-HT1E (11), as well as 5-HT2A (12, 13) and 5-HT2C (14, 15), which have lower affinities for 5-HT than the other serotonin receptors. The 5-HT4 receptor was also one of the early 5-HT receptor subtypes identified mainly by radioligand binding and pharmacological studies (refs. 16, 17, and see Figure 1).
In terms of signal transduction and pharmacology, we now know that all members of the 5-HT1 family are intronless and couple to the Gi family of heterotrimeric G proteins — in keeping with the original description of the 5-HT1A receptor (7). The 5-HT1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Table 1), which is a selective 5-HT1A partial agonist. Likewise, 5-HT1B and 5-HT1D receptors represent canonical targets for antimigraine medications including various ergots (e.g., ergotamine, dihydroergotamine, and methysergide) as well as the more selective tryptans (e.g., sumatryptan and analogs) (18, 19). No selective 5-HT1E drugs exist and though selective 5-HT1F drugs have been developed, none of them have yet been approved by the FDA (Table 1). Theoretically, 5-HT1F antagonists might represent novel therapeutic agents for migraine headaches.
Listed are approved/investigational drugs targeting distinct 5-HT receptor subtypes
The 5-HT2 family receptors couple to Gq G proteins and modulate phosphoinositide hydrolysis and PKC activation (20–22). 5-HT2 family receptors typically have lower affinity for molecular serotonin than other 5-HT receptors and are often potently inhibited by both typical (12) and atypical (23) antipsychotic drugs (24). 5-HT2A receptors represent the main serotonin receptors found in platelets, vascular smooth muscle, and the cerebral cortex (25, 26). As discussed below, 5-HT2B receptors are enriched in the heart (27), and drugs likely mediate their valvulopathogenic actions on heart valves via a combination of G protein and β-arrestin signaling (27–29). The distribution and function of 5-HT2C receptors will be summarized below when lorcaserin, a selective 5-HT2C agonist, is discussed.
The 5-HT4, 5-HT6, and 5-HT7 families of receptors are all coupled to the Gs G proteins and mediate the stimulatory effects of serotonin on cAMP accumulation. 5-HT4 receptors represent the main site of action of many drugs used for treating gastrointestinal motility disorders (Table 1) and are found widely distributed throughout the body (18). 5-HT6 and 5-HT7 receptors have recently been the subject of intense investigation by pharmaceutical companies based on the discovery that many atypical antipsychotic drugs have high affinities for both receptors (30). As can be seen in Table 1, compounds that target 5-HT6 and 5-HT7 receptors are currently in testing for depression, cognition enhancement, and psychosis.
Drugs acting on 5-HT receptors display a range of efficacy from full agonists to inverse agonists (e.g., antagonists with negative intrinsic activity). Buspiron, for instance, is a partial agonist at 5-HT1A receptors, whereas sumatriptan is a full agonist at 5-HT1D receptors. By contrast, both typical and atypical antipsychotic drugs have inverse agonist actions at many 5-HT receptor subtypes including 5-HT2A (31) and 5-HT2C (32). Inverse agonists represent drugs that antagonize the action of full agonists (e.g., are “antagonists”) and simultaneously lower the basal level of receptor signaling (e.g., suppress constitutive receptor activity; see ref. 33 for review). Essentially, inverse agonists are antagonists with negative intrinsic activity. Finally, drugs like ergotamine display functional selectivity or signaling bias for many 5-HT receptors including 5-HT2B (28, 29). Thus, ergotamine has much higher potency for activating β-arrestin pathways than for activating G protein–mediated signaling (28, 29) and as such is considered to display functional selectivity for β-arrestin signaling and to represent a β-arrestin–biased agonist.
Because of the vast effort devoted over the past five decades to studying serotonin and classifying its receptors, we now appreciate that serotonin is involved in the regulation of nearly every CNS function, including cognition, autonomic function, perception, emotion, appetite, aggression, and mood, to name but a few (18). Additionally, alterations in serotonergic neurotransmission have been implicated in nearly every neuropsychiatric disorder, including schizophrenia and related psychotic disorders, major depression, eating disorders, and so on (18). Many of the therapeutic actions, as well as serious side effects of commonly prescribed medications, are due to nonspecific actions on 5-HT receptor subtypes (18, 27, 34). Given this wealth of evidence implicating altered serotonergic neurotransmission in neuropsychiatric disease, as well as the plethora of 5-HT receptor subtypes, it has long been proposed that drugs that target distinct 5-HT receptors might provide novel and effective treatments for many neuropsychiatric disorders (Table 1).
Despite the abundant evidence suggesting that selective serotonergic drugs would prove efficacious for many diseases, a fundamental challenge encountered for creating them relates to the relatively similar binding pocket shared among 5-HT receptor subtypes. As seen in recent high-resolution structures derived from the pharmacologically distinct 5-HT1B and 5-HT2B receptors (refs. 19, 29, and Figure 2), many of the key amino acids essential for ligand binding by the G protein–coupled 5-HT receptors are identical. Until recently, this high degree of structural conservation made it challenging for medicinal chemists to create subtype-selective 5-HT receptor–active drugs. As is evident from Table 1, and as has been briefly reviewed earlier, several selective serotonergic drugs have now survived the gauntlet of clinical trials and are approved for treating a number of diseases, including obesity, migraine headaches, psychosis, anxiety, depression, chemotherapy-induced nausea, and even Alzheimer’s disease.
Structures of lorcaserin and pimavanserin in relationship to the serotonin receptor–binding pocket. Shown at the top are the structures of lorcaserin ((1_R_)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1_H_-3-benzazepine) and pimavanserin (_N_-(4-fluorophenylmethyl)-_N_-(1-methylpiperidin-4-yl)-_N_′-(4-(2-methylpropyloxy)phenylmethyl)carbamide), and shown below is the consensus-binding pocket of 5-HT receptors.
In this review, we focus on one newly approved 5-HT2C–selective antiobesity medication (lorcaserin) and a 5-HT2A–selective inverse agonist with efficacy in the dopamine-dependent psychosis of Parkinson’s disease (pimavanserin) that has recently been selected for expedited FDA review (see Figure 2 for structures). Currently, there is no approved treatment for this relatively common disorder. Clozapine and quetiapine, which are nonselective inverse agonists at the 5-HT2A receptor are rarely used because of unwanted side effects caused by their actions at other receptors (35).