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Marcello Leopoldo - One of the best experts on this subject based on the ideXlab platform.
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structural modifications of the serotonin 5 ht7 Receptor agonist n 4 cyanophenylmethyl 4 2 biphenyl 1 piperazinehexanamide lp 211 to improve in vitro microsomal stability a case study
European Journal of Medicinal Chemistry, 2016Co-Authors: Enza Lacivita, Roberto Perrone, Sabina Podlewska, Luisa Speranza, Mauro Niso, Grzegorz Satala, Carla Perronecapano, Andrzej J Bojarski, Marcello LeopoldoAbstract:The 5-HT7 serotonin Receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 Receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 Receptors and showed selectivity towards 5-HT6 and dopamine D2 Receptors and different selectivity for 5-HT1A and α1 adrenergic Receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 Receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 Receptor in vivo.
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GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B Receptors involved?
Journal of cardiovascular pharmacology, 2015Co-Authors: Carolina Sánchez-maldonado, Marcello Leopoldo, Enza Lacivita, Pedro López-sánchez, Liliana Anguiano-robledo, José A. TerrónAbstract:The 5-HT1B/1D Receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 Receptor agonist, and 5-HT5A/5B Receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D Receptor antagonists. Also, expression of 5-HT5A and 5-HT5B Receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D Receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 Receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 Receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B Receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 Receptors. This mechanism, however, resembles putative 5-HT5B Receptors.
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activation of 5 ht7 serotonin Receptors reverses metabotropic glutamate Receptor mediated synaptic plasticity in wild type and fmr1 knockout mice a model of fragile x syndrome
Biological Psychiatry, 2012Co-Authors: Lara Costa, Marcello Leopoldo, Enza Lacivita, Michela Spatuzza, Simona Dantoni, Carmela M Bonaccorso, Chiara Trovato, S A Musumeci, Maria Vincenza Catania, Lucia CirannaAbstract:Background Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate Receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) Receptors; the underlying mechanisms are unknown. Methods We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate Receptor surface expression. Results Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A Receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 Receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 Receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate Receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA Receptors, an effect antagonized by SB-269970. Conclusions Serotonin 7 Receptor activation reverses metabotropic glutamate Receptor-induced AMPA Receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 Receptors may represent a novel strategy in the therapy of FXS.
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lp 211 is a brain penetrant selective agonist for the serotonin 5 ht7 Receptor
Neuroscience Letters, 2010Co-Authors: Peter B Hedlund, Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Silvio Caccia, Gor Sarkisyan, Claudia Fracasso, Giuliana Martelli, Roberto PerroneAbstract:We have determined the pharmacological profile of the new serotonin 5-HT7 Receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT Receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 Receptor (5-HT7−/−) and their 5-HT7+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 Receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT Receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7−/− mice. Our results suggest that LP-211 can be used as a 5-HT7 Receptor agonist in vivo.
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5 ht7 Receptor modulators a medicinal chemistry survey of recent patent literature 2004 2009
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
Roberto Perrone - One of the best experts on this subject based on the ideXlab platform.
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structural modifications of the serotonin 5 ht7 Receptor agonist n 4 cyanophenylmethyl 4 2 biphenyl 1 piperazinehexanamide lp 211 to improve in vitro microsomal stability a case study
European Journal of Medicinal Chemistry, 2016Co-Authors: Enza Lacivita, Roberto Perrone, Sabina Podlewska, Luisa Speranza, Mauro Niso, Grzegorz Satala, Carla Perronecapano, Andrzej J Bojarski, Marcello LeopoldoAbstract:The 5-HT7 serotonin Receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 Receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 Receptors and showed selectivity towards 5-HT6 and dopamine D2 Receptors and different selectivity for 5-HT1A and α1 adrenergic Receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 Receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 Receptor in vivo.
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lp 211 is a brain penetrant selective agonist for the serotonin 5 ht7 Receptor
Neuroscience Letters, 2010Co-Authors: Peter B Hedlund, Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Silvio Caccia, Gor Sarkisyan, Claudia Fracasso, Giuliana Martelli, Roberto PerroneAbstract:We have determined the pharmacological profile of the new serotonin 5-HT7 Receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT Receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 Receptor (5-HT7−/−) and their 5-HT7+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 Receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT Receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7−/− mice. Our results suggest that LP-211 can be used as a 5-HT7 Receptor agonist in vivo.
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5 ht7 Receptor modulators a medicinal chemistry survey of recent patent literature 2004 2009
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
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5-HT7 Receptor modulators: a medicinal chemistry survey of recent patent literature (2004 – 2009)
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
Y S Chan - One of the best experts on this subject based on the ideXlab platform.
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5 ht1a Receptor mediated attenuation of synaptic transmission in rat medial vestibular nucleus impacts on vestibular related motor function
The Journal of Physiology, 2020Co-Authors: Lei Han, Puiyi Kwan, Oscar Wingho Chua, Daisy K Y Shum, Y S ChanAbstract:KEY POINTS Chemogenetic activation of medial vestibular nucleus-projecting 5-HT neurons resulted in deficits in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. The 5-HT1A Receptor mediates the vestibular-related behavioural effects of 5-HT in the vestibular nucleus. 5-HT1A Receptor activation attenuated evoked excitatory postsynaptic currents and evoked inhibitory postsynaptic currents via a presynaptic mechanism in the vestibular nucleus. ABSTRACT While the anxiolytic effects of serotonergic neuromodulation are well studied, its role in sensorimotor coordination and postural control is unclear. In this study, we show that an increase of serotonin (5-hydroxytryptamine, 5-HT) at the medial vestibular nucleus (MVN), a brainstem centre for vestibulospinal coordination, by either direct cannula administration or chemogenetic stimulation of MVN-projecting serotonergic neurons, adversely affected performance of rats in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. Application of the 5-HT1 and 5-HT7 Receptor co-agonist 8-hydroxy-2-(di-n-propylamino) tetralin recapitulated the effect of 5-HT, while co-administration of the specific 5-HT1A Receptor antagonist WAY 100135 effectively abolished all 5-HT-induced behavioural deficits. This indicated that 5-HT1A Receptors mediated the effects of 5-HT in the rat MVN. Using whole-cell patch-clamp recording, we demonstrated that 5-HT1A Receptor activation attenuated both evoked excitatory and evoked inhibitory postsynaptic currents through a presynaptic mechanism in the rat MVN. The results thus highlight the 5-HT1A Receptor as the gain controller of vestibular-related brainstem circuits for posture and balance.
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5‐HT 1A Receptor‐mediated attenuation of synaptic transmission in rat medial vestibular nucleus impacts on vestibular‐related motor function
The Journal of physiology, 2020Co-Authors: Lei Han, Puiyi Kwan, Daisy K Y Shum, Oscar Wing‐ho Chua, Y S ChanAbstract:KEY POINTS Chemogenetic activation of medial vestibular nucleus-projecting 5-HT neurons resulted in deficits in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. The 5-HT1A Receptor mediates the vestibular-related behavioural effects of 5-HT in the vestibular nucleus. 5-HT1A Receptor activation attenuated evoked excitatory postsynaptic currents and evoked inhibitory postsynaptic currents via a presynaptic mechanism in the vestibular nucleus. ABSTRACT While the anxiolytic effects of serotonergic neuromodulation are well studied, its role in sensorimotor coordination and postural control is unclear. In this study, we show that an increase of serotonin (5-hydroxytryptamine, 5-HT) at the medial vestibular nucleus (MVN), a brainstem centre for vestibulospinal coordination, by either direct cannula administration or chemogenetic stimulation of MVN-projecting serotonergic neurons, adversely affected performance of rats in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. Application of the 5-HT1 and 5-HT7 Receptor co-agonist 8-hydroxy-2-(di-n-propylamino) tetralin recapitulated the effect of 5-HT, while co-administration of the specific 5-HT1A Receptor antagonist WAY 100135 effectively abolished all 5-HT-induced behavioural deficits. This indicated that 5-HT1A Receptors mediated the effects of 5-HT in the rat MVN. Using whole-cell patch-clamp recording, we demonstrated that 5-HT1A Receptor activation attenuated both evoked excitatory and evoked inhibitory postsynaptic currents through a presynaptic mechanism in the rat MVN. The results thus highlight the 5-HT1A Receptor as the gain controller of vestibular-related brainstem circuits for posture and balance.
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Activation of 5-HT7 Receptors reverses NMDA Receptor-dependent LTD by activating PKA at medial vestibular neurons
'Elsevier BV', 2017Co-Authors: Han L, Y S ChanAbstract:The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus. We therefore aim to determine the action of 5-HT on the LTD of type B MVN neurons and elucidate the relevant 5-HT Receptor subtypes responsible for its action. Using specific agonists and antagonists of 5-HT Receptors, we found that selective activation of 5-HT7 Receptor in type B neurons in the MVN of juvenile (P13-16) rats completely abolished NMDA-Receptor-mediated LTD in a protein kinase A (PKA)-dependent manner. Our finding that 5-HT restricts plasticity of type B MVN neurons via 5-HT7 Receptors offers a mechanism whereby vestibular tuning contributes to the maturation of the vestibulo-spinal circuit and highlights the role of 5-HT in postural control
Enza Lacivita - One of the best experts on this subject based on the ideXlab platform.
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structural modifications of the serotonin 5 ht7 Receptor agonist n 4 cyanophenylmethyl 4 2 biphenyl 1 piperazinehexanamide lp 211 to improve in vitro microsomal stability a case study
European Journal of Medicinal Chemistry, 2016Co-Authors: Enza Lacivita, Roberto Perrone, Sabina Podlewska, Luisa Speranza, Mauro Niso, Grzegorz Satala, Carla Perronecapano, Andrzej J Bojarski, Marcello LeopoldoAbstract:The 5-HT7 serotonin Receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 Receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 Receptors and showed selectivity towards 5-HT6 and dopamine D2 Receptors and different selectivity for 5-HT1A and α1 adrenergic Receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 Receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 Receptor in vivo.
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GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B Receptors involved?
Journal of cardiovascular pharmacology, 2015Co-Authors: Carolina Sánchez-maldonado, Marcello Leopoldo, Enza Lacivita, Pedro López-sánchez, Liliana Anguiano-robledo, José A. TerrónAbstract:The 5-HT1B/1D Receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 Receptor agonist, and 5-HT5A/5B Receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D Receptor antagonists. Also, expression of 5-HT5A and 5-HT5B Receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D Receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 Receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 Receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B Receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 Receptors. This mechanism, however, resembles putative 5-HT5B Receptors.
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activation of 5 ht7 serotonin Receptors reverses metabotropic glutamate Receptor mediated synaptic plasticity in wild type and fmr1 knockout mice a model of fragile x syndrome
Biological Psychiatry, 2012Co-Authors: Lara Costa, Marcello Leopoldo, Enza Lacivita, Michela Spatuzza, Simona Dantoni, Carmela M Bonaccorso, Chiara Trovato, S A Musumeci, Maria Vincenza Catania, Lucia CirannaAbstract:Background Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate Receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) Receptors; the underlying mechanisms are unknown. Methods We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate Receptor surface expression. Results Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A Receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 Receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 Receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate Receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA Receptors, an effect antagonized by SB-269970. Conclusions Serotonin 7 Receptor activation reverses metabotropic glutamate Receptor-induced AMPA Receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 Receptors may represent a novel strategy in the therapy of FXS.
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lp 211 is a brain penetrant selective agonist for the serotonin 5 ht7 Receptor
Neuroscience Letters, 2010Co-Authors: Peter B Hedlund, Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Silvio Caccia, Gor Sarkisyan, Claudia Fracasso, Giuliana Martelli, Roberto PerroneAbstract:We have determined the pharmacological profile of the new serotonin 5-HT7 Receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT Receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 Receptor (5-HT7−/−) and their 5-HT7+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 Receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT Receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7−/− mice. Our results suggest that LP-211 can be used as a 5-HT7 Receptor agonist in vivo.
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5 ht7 Receptor modulators a medicinal chemistry survey of recent patent literature 2004 2009
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
Francesco Berardi - One of the best experts on this subject based on the ideXlab platform.
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lp 211 is a brain penetrant selective agonist for the serotonin 5 ht7 Receptor
Neuroscience Letters, 2010Co-Authors: Peter B Hedlund, Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Silvio Caccia, Gor Sarkisyan, Claudia Fracasso, Giuliana Martelli, Roberto PerroneAbstract:We have determined the pharmacological profile of the new serotonin 5-HT7 Receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT Receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 Receptor (5-HT7−/−) and their 5-HT7+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 Receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT Receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7−/− mice. Our results suggest that LP-211 can be used as a 5-HT7 Receptor agonist in vivo.
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5 ht7 Receptor modulators a medicinal chemistry survey of recent patent literature 2004 2009
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
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5-HT7 Receptor modulators: a medicinal chemistry survey of recent patent literature (2004 – 2009)
Expert Opinion on Therapeutic Patents, 2010Co-Authors: Marcello Leopoldo, Enza Lacivita, Francesco Berardi, Roberto PerroneAbstract:Importance of the field: The 5-HT7 Receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT7 Receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT7 Receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT7 Receptor modulators.Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT7 Receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT7 Receptor and also the differ...
