Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease

Price, D. L.; Bonhaus, Douglas W.; McFarland, Krista

doi:10.1097/fbp.0b013e3283566082

Cited by 32 publications

(21 citation statements)

References 25 publications

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“…Interestingly, applications of 5-HT 2 receptor inverse agonists have recently extended beyond schizophrenia. For example, in addition to psychosis associated with Parkinson’s disease [86], 5-HT 2 receptor inverse agonists are also being evaluated as treatments for psychosis related to Alzheimer’s disease [85] and for treatment of movement disorders related to Parkinson’s disease [87]. Overall, a better understanding of inverse agonism at 5-HT 2 receptor systems could have far-reaching implications for the development of novel therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Atypical antipsychotics and inverse agonism at 5-HT<sub>2</sub> receptors

Sullivan¹,

Clarke²,

Berg³

2015

CPD

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It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or “constitutive” receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for the treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT2A and 5-HT2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of antipsychotic drugs may provide new avenues for drug development.

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Section: Discussionmentioning

confidence: 99%

Atypical antipsychotics and inverse agonism at 5-HT<sub>2</sub> receptors

Sullivan¹,

Clarke²,

Berg³

2015

CPD

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“…It is unlikely that CBD exerts its therapeutic effects through 5-HT 2A receptor activation, as CBD has never been shown to exert psychotropic effects. Thus, involvement of 5-HT 2A in the antipsychotic effect of CBD is unlikely [273].…”

Section: Cbd Receptor Targets In Psychosismentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

447

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…The FDA subsequently indicated that it will evaluate a new drug application (NDA) from ACADIA on the basis of these two studies and other safety data (65). Preclinical studies indicate that pimavanserin may also be useful for treating the psychosis of Alzheimer's disease (66). Pimavanserin has also been shown to potentiate a subeffective dose of the atypical APD risperidone in acutely psychotic patients with schizophrenia, producing a more rapid onset of action than standard-dose risperidone or an equally effective dose of haloperidol, while producing fewer side effects (67).…”

Section: Treating Parkinson's Disease Psychosis: From Clozapine To Pimentioning

confidence: 99%

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

Meltzer¹,

Roth²

2013

J. Clin. Invest.

103

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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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Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease

Cited by 32 publications

References 25 publications

Atypical antipsychotics and inverse agonism at 5-HT<sub>2</sub> receptors

Atypical antipsychotics and inverse agonism at 5-HT<sub>2</sub> receptors

Molecular Targets of Cannabidiol in Neurological Disorders

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

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