Affinity For Serotonin 5-HT2A Receptors Research Articles

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential. In our previous studies, we selected a multimodal compound, HBK-15, which showed a fast antidepressant-like effect in animal models of depression. HBK-15 demonstrated a high affinity for serotonin 5-HT1A receptors and moderate for 5-HT7, dopamine D2, and α1-adrenoceptors. Based on the receptor profile and preliminary studies, we aimed to investigate the anxiolytic potential of HBK-15 using the conditioned-response rat model of anxiety, i.e., the Vogel drinking test. We performed hot plate and free-drinking tests to exclude false positive results in the Vogel test. Using radioligand binding studies, we also investigated the affinity of the compound for the selected biological targets, which play a role in anxiety. Our experiments revealed that HBK-15 showed an anxiolytic-like effect in rats (5 mg/kg) without influencing the pain threshold or the amount of water consumed in the free-drinking test. Furthermore, the tested compound did not show a significant affinity for the selected biological targets, which suggests that its anxiolytic-like mechanism of action could be connected with the interaction with other receptors. This study indicates that multimodal compounds with a receptor profile similar to HBK-15 could be an attractive therapeutic option for patients with a generalized anxiety disorder. However, more studies are required to determine the exact mechanism of action of HBK-15 and its safety profile.

Treatment of Cognitive Impairment in Schizophrenia

Cognitive function in schizophrenia is one of the main elements significantly related to functional outcomes, accounting for approximately 25–50% of the variance in real-world functioning. Treatment approaches to cognitive dysfunctions include both pharmacological and psychosocial interventions. Second Generation Antipsychotics (SGAs) may partially improve cognitive dysfunction, due to their relatively high affinity for serotonin 5HT2A receptors. The effects of glutamatergic agents indicated benefits on cognition of a group of amino acids that act as glutamate agonists by binding to the glycine site on NMDA receptors. The administration of muscarinic antagonists potentiates cognitive impairments, while the α7 nicotinic acetylcholine receptors have been shown to play an important role in cognition with potential therapeutic applications in schizophrenia. Studies on drugs targeting neuroinflammation and oxidative stress emerged. Cognitive remediation has proved to be effective in improving cognitive dysfunctions and psychosocial functioning in people with schizophrenia, however there is still a limited understanding of how the putative active therapy ingredients contribute to changes in the brain and translate into improved real-world functioning. Cogrem exerts its maximal benefit when delivered in the context of other psychiatric rehabilitative interventions, but it is not yet clear what are the mechanisms of effectiveness of integrated treatment. It is important that future research shift from studies of group efficacy to individual efficacy of treatments, in the perspective of precision medicine. Issues related to individual predictors of effectiveness and of interactions between specific pharmacologic, specific cognitive remediation technique and individual patients’ characteristics should be furtherly addressed.DisclosureIn the last two years, Prof Vita received, directly or indirectly, support for clinical studies or trials, conferences, consultancies, Congress presentations, advisory boards from: Angelini, Boehringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck,

Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus.

A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (alpha1 and alpha2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin receptors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, alpha1 and alpha2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (Ki = 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.

Identification of a serotonin/glutamate receptor complex implicated in psychosis

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.

Risperidone and Dysphagia in a Developmentally Disable Woman

Sir: Dysphagia represents an infrequently reported adverse effect secondary to use of neuroleptic agents.1 The presentation of dysphagia is often associated with parkinsonian symptoms.2 Autonomic dysfunction is due to changes in the hypothalamus, locus ceruleus, dorsal vagal nucleus, and sympathetic ganglia.3 Neuroleptic medications may induce swallowing difficulties by similar mechanisms.1 Atypical antipsychotic agents are believed to have a more advantageous side effect profile with fewer extrapyramidal effects.1 This medication-mediated reversible effect may be underdiagnosed in populations with additional neurologic impairments. Case report. Ms. A, a 60-kg, 46-year-old white woman diagnosed with dementia due to lithium toxicity and profound mental retardation (IQ = 20), resides in a state-run facility. Her verbal ability is limited to single words. The patient has a long-standing history of aggression and aberrant behaviors addressed with behavioral interventions and medication use. She presented to the psychiatric clinic in September 2006 with a significant increase in drooling, difficulty swallowing, and gurgling sounds. The total daily doses for the psychoactive medication regimen at the time dysphagia was diagnosed included risperidone 2 mg daily for psychosis and mood lability, clozapine 500 mg for mood lability, clonidine 0.3 mg for aggression and dyskinesia, and benztropine 1 mg for drooling and extrapyramidal symptoms. The most recent medication change, which occurred the previous month, was an increase in risperidone from 1.5 mg to 2 mg that followed increases in behavioral dyscontrol without an identifiable antecedent. In clinic, Ms. A was not appreciably calmer. The dose was subsequently decreased to the previous dose of 1.5 mg. On follow-up 3 days later, drooling and swallowing difficulties were resolving. Case reports related to dysphagia secondary to atypical antipsychotic use have been reported previously. Two reports involved risperidone use; one followed an increase to a total daily dose of 1.5 mg and resolved with risperidone discontinuation and substitution of olanzapine 2.5 mg.1 The other occurred following a single 4-mg risperidone dose and resolved after administration of benztropine.4 Dysphagia was also reported 5 days after initiation of olanzapine 20 mg.5 Olanzapine-associated dysphagia resolved with medication discontinuation. Concurrent use of clozapine and risperidone may have predisposed our patient to adverse effects. Clozapine atypicality is thought to be associated with its greater affinity for serotonin 5-HT2A receptors than dopamine D2 receptors and rapid dissociation from the basal ganglia D2 receptors. In addition, its anticholinergic effects may act to moderate the risk of extrapyramidal effects.6 Risperidone has pharmacologic properties resembling those of clozapine, with antagonistic activity primarily at serotonin 5-HT2A and dopamine D2 receptors.7 Concurrent therapy may negatively impact the rapid D2 dissociation times that have been reported8 and increase the potential for adverse effects. We believe this is the first report of dysphagia identified secondary to atypical antipsychotic use in a person with developmental disabilities. The presence of mental retardation is an indication of neurologic impairment, and dysphagia may be overlooked.9 Limited verbal abilities may impede self-reporting. Clinicians should be aware of the potential for this infrequently reported adverse effect in both the general population and those with developmental disabilities, particularly with concurrent therapy regimens.

Neuroleptic Malignant Syndrome Associated with Quetiapine

INTRODUCTION Neuroleptic malignant syndrome is a rare adverse effect of antipsychotic agents. The most common signs and symptoms are hyperthermia, muscle rigidity, changes in mental status, and autonomic instability.1 The prevalence of neuroleptic malignant syndrome in association with the use of typical antipsychotics is estimated at 0.5% to 1%.1 Atypical antipsychotics such as quetiapine have greater affinity for serotonin 5-HT2A receptors than for dopamine D2 receptors. Therefore, it is believed that atypical antipsychotics are less likely to cause this condition. This article describes a patient treated with quetiapine who presented with biochemical and clinical evidence of neuroleptic malignant syndrome.

Interaction of the novel antipsychotic drug amperozide and its metabolite FG5620 with central nervous system receptors and monoamine uptake sites: Relation to behavioral and clinical effects

Behavioral, biochemical, and electrophysiological studies suggest that amperozide affects mesolimbic and mesocortical dopamine neurotransmission. The receptor binding profile of amperozide is discussed and related to behavioral and clinical, i.e., antipsychotic, effects of the drug. As previously reported, amperozide displayed high affinity for serotonin 5-HT2A receptors (Ki = 16 nmol/L), and moderate affinity for striatal dopamine D2 (Ki = 540 nmol/L) and cortical alpha 1-adrenergic receptors (Ki = 172 nmol/L). In the present study amperozide displayed low affinity for several serotonin receptor subtypes as well as for the dopamine D4 receptor transfected in COS7 cells (Ki D4.2 = 769 nmol/L and Ki D4.4 = 384 nmol/L). Amperozide was very weak or did not interact with several other receptor species including adrenergic, histaminergic, muscarinic, benzodiazepine, gamma-aminobutyric acid, amino acid, opiate, and Ca channels; however, amperozide was found to compete for [3H]paroxetine binding for the serotonin transporter in the nanomolar range (Ki = 49 nmol/L). In vitro and in vivo binding potency of amperozide correlates best with behavioral effects, indicating 5-HT2A antagonism, although serotonin uptake inhibition may contribute to the effects of amperozide on dopamine neurotransmission. The metabolite of amperozide, FG5620, displayed 5-10 times lower pharmacologic activity than amperozide. These properties of amperozide may suggest that the antipsychotic effects of amperozide are mediated by 5-HT2A receptors, although 5-HT uptake inhibition and alpha 1-adrenergic receptor-mediated effects may be considered, particularly at higher doses.