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An Orally Active Phenylaminotetralin-Chemotype Serotonin 5‑HT7 and 5‑HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Although two drugs (the antipsychotic medications, risperidone and aripiprazole) are approved to treat irritability associated with autism spectrum disorder (ASD), there are no drugs approved to treat core symptoms of ASD, which include deficits in social communication as well as restricted and repetitive patterns of behavior, such as stereotypy. Stereotypy is observed as uncontrolled, rigid and repetitive, low-order, motor behavior, e.g., hand waving and body rocking, and is considered the most robust diagnostic marker of ASD in children. Despite the severe impact stereotypy has on daily life functioning for persons with ASD and its close correlation with cognitive and attention defi cits, it has received relatively scant attention regarding development of drug therapy…

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A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

Psychotic disorders, which affect approximately 3% of the population (Perala et al., 2007), are associated with an overactive striatal dopamine system (Abi-Dargham et al., 1998; Seeman and Seeman, 2014). Specifically, persons with schizophrenia are hypersensitive to psychostimulants (Curran et al., 2004), show elevated psychostimulant-induced dopamine release (Abi-Dargham et al., 1998), and display increased presynaptic dopamine synthesis in the striatum (Seeman and Seeman, 2014). Most existing antipsychotic medications interact primarily with dopamine D2 receptors to, theoretically, normalize dopamine signaling…

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The serotonin-2 receptor modulator, (-)-trans-PAT, decreases voluntary ethanol consumption in rats

Agonism of serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptors has been shown to decrease voluntary ethanol consumption in rats (Tomkins et al., 2002). However, as evidenced by the recent FDA approval of lorcaserin for weight loss, 5-HT2C receptor agonism also has anorexiant effects (Garfield and Heisler, 2009). The 5-HT2C receptor agonist Ro60-0175 demonstrates only a 2–3-fold dose separation for inhibition of ethanol consumption versus food consumption (Higgins and Fletcher, 2003). Additionally, Ro60-0175 has only 30-fold selectivity for activating the 5-HT2C receptors over the structurally related 5-HT2A receptors (Porter et al., 1999), which cause unwanted psychotomimetic effects (Nichols, 2004). Thus it is important to test selective 5-HT2C receptor agonists and assess their inhibitory effects on ethanol self-administration compared to that of other caloric substances…

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Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: Potential utility as antipsychotic medications

Brain dopamine and serotonin systems have long been thought to be involved in the pathophysiology and pharmacotherapy of schizophrenia and other psychoses. For example, the dopamine hypothesis of schizophrenia arose from observations that the first relatively safe and effective antipsychotic drugs, the phenothiazines (e.g., chlorpromazine) in the early 1950s, affect brain dopamine metabolism (Carlsson and Lindquist, 1963). Neuroleptics such as chlorpromazine and the butyrophenone haloperidol “take hold” (lepsis) of the central nervous system (CNS) to suppressmovement as well as other behavior, and resulting debilitating extrapyramidal movement side effects are implicit in the clinical definition of neuroleptic antipsychotic drugs…

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A Novel Serotonin-2 (5-HT2) Modulator as a Candidate Drug to Treat Impulsive Behavioral Disorders and Psychoses without Weight Gain as a Side Effect

It is hypothesized that the desired serotonin 5-HT2 receptor pharmacology required to treat impulsive behavioral disorders, including, psychostimulant abuse/addiction and binge eating, as well as, psychoses, is 5-HT2A antagonism and/or 5-HT2C agonism. Currently, however, no selective 5-HT2A antagonist has demonstrated clinical efficacy to treat psychostimulant addiction or psychoses, and a clinically-acceptable 5-HT2C agonist that does not also activate 5-HT2A (hallucinations) and/or 5-HT2B (cardiopulomonary toxicity) receptors has not been reported…

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Effect of (−)-trans-PAT, a novel 5-HT2C receptor agonist, on intake of palatable food in mice

Increased activation of brain serotonin (5-HT) receptors reduces food intake in animals and humans (Halford et al., 2007); these receptors are therapeutic targets to prevent overeating. The 14 mammalian serotonin receptor subtypes are grouped into the 5-HT1–5-HT7 families (SandersBush and Mayer, 2006). The 5-HT2 receptor family consists of the 5-HT2A, 5-HT2B, and 5-HT2C membrane-bound G protein-coupled receptors (GPCRs) that signal primarily through Gαq protein to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol second messengers (Raymond et al., 2001). The human 5-HT2C receptor (Saltzman et al.,1991) is found exclusively in brain where it is expressed in many regions and seems to be involved in several physiological or psychological processes, including eating behavior (Tecott et al., 1995)…

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