Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Abstract

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT 2C and 5HT 2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively. Serotonin receptors and signal transductionSerotonin, 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-HT 1 and 5-HT 2 families of receptors ( Figure 1).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-HT 1A (5), the first socalled 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-HT 1B/1D (10) and 5-HT 1E (11), as well as 5-HT 2A (12, 13) and 5-HT 2C (14, 15), which have lower affinities for 5-HT than the other serotonin receptors. The 5-HT 4 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-HT 1 family are intronless and couple to the Gi family of heterotrimeric G proteins -in keeping with the original description of the 5-HT 1A receptor (7). The 5-HT 1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Tabl...

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