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RationaleSamelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability.ObjectivesPharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy.MethodsSamelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep–wake cycle and cataplexy.ResultsSamelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice.ConclusionsPre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.

Background SUVN‐I7016031 is a novel and selective positive allosteric modulator (PAM) of the M1 subtype of the muscarinic acetylcholine receptors (mAChRs). The proposed primary indication for SUVN‐I7016031 is in the treatment of dementia such as Alzheimer’s disease dementia (ADD) and Parkinson’s disease dementia (PDD). In the current research, the pharmacological properties of SUVN‐I7016031 in various types of dementia were investigated. Method SUVN‐I7016301 was characterized using a calcium mobilization assay. The binding affinity towards the orthosteric M1 ‐ M5 site was investigated. The effect of SUVN‐I7016031 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I7016031 were studied both in rodent and non‐rodent species. The effect of SUVN‐I7016031 on MK‐801 induced memory deficits in rats using object recognition task (ORT) and on time‐induced social memory deficits in rats using social recognition task (SRT) was studied. The efficacy of SUVN‐I7016031 in a rat model of PDD was investigated. The effects of SUVN‐I7016031 (10‐60 mg/kg, p.o.) on inositol 1 phosphate (IP‐1) levels were studied in rats. Result Functionally, SUVN‐I7016031 was found to be a positive allosteric modulator at the M1 receptor with an allosteric potency EC50 of 355 nM. In hippocampal slice electrophysiology studies, the EC50 and EC30 values were ∼527 nM and ∼326 nM, respectively. No significant binding towards the orthosteric site at the muscarinic M1 to M5 receptor was observed. SUVN‐I7016031 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I7016031 was found to have brain penetration properties with adequate free fraction. SUVN‐I7016031 reversed delay‐induced memory disruption in adult rats in a SRT and antagonized MK‐801 induced memory disruption in ORT. SUVN‐I7016031 was found to reverse haloperidol induced memory deficits, a rat model of PDD. Treatment with SUVN‐I7016031 produced a significant increase in striatal inositol 1‐phosphate (IP‐1) levels in rats, providing in‐vivo support for the activation of M1 mAChRs by SUVN‐I7016031. Conclusion SUVN‐I7016031 is a novel, potent, and selective M1‐PAM that demonstrated pro‐cognitive effects in animal models of PDD and ADD.

Introduction Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor (H3R) inverse agonist with hH3 Ki of 8.7 nM. Samelisant exhibited desired pharmacokinetic properties and favorable brain penetration in rodents. Preclinical studies demonstrated samelisant produced wake promoting and anticataplectic effects in orexin knockout mice. Additionally samelisant modulated neurotransmitters like histamine in brain indicating neurochemical basis for wake promoting effects. Excessive daytime sleepiness (EDS) estimated to affect 20-50% of patients with Parkinson’s disease (PD). Although non-treated PD patients exhibit EDS and sleep attacks, it is often associated with use of dopamine (DA) agonists, especially the recent non-ergot DA D2/3 agonists. Samelisant is currently being evaluated in a Phase-2 study as monotherapy for the treatment of EDS in patients with narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Hemiparkinsonism was induced in male Wistar rats by injecting 6-OHDA (12 µg/4 µL) unilaterally into the medial forebrain bundle, and telemetric device was implanted to monitor EEG, EMG and activity. Animals were allowed to recover for 3 weeks prior to initiating EEG recordings. Basal EEG was recorded for 1 hour prior to samelisant administration and EEG acquisition was continued for 6 hours post treatment. After a washout period of 1 week, rats were administered with the quinpirole (30 µg/kg, i.p.) followed by samelisant and EEG acquisition was continued for 6 hours. EEG recordings were processed for sleep stages using NeuroScore and sleep sign software (DSI, MN, USA). Results Hemiparkinsonian animals showed decrease in wake and increase in sleep time during dark phase. Treatment with samelisant (10 and 30 mg/kg, p.o.) produced significant increase in cumulative wake period during first 3 hours post treatment. Treatment with quinpirole in hemiparkinsonian rats produced decrease in wake and increase in sleep time. Treatment with samelisant produced dose- dependent increase in wake with decrease in REM and NREM periods in quinpirole treated hemiparkinsonian rats. Conclusion The results from current preclinical studies indicate that samelisant may have a potential utility for the treatment of excessive daytime sleepiness in PD patients. Support (if any)

SUVN-I6107 is a novel and selective muscarinic M1 Positive Allosteric Modulator (PAM) being developed for the treatment of dementia due to neurodegenerative disorders. In the current research, the pharmacological properties of SUVN-I6107 in various animal models of cognitive deficits were investigated. SUVN-I6107 was characterized using a calcium mobilization assay and the binding affinity towards the orthosteric M1 - M5 site was investigated to assess the selectivity. The effect of SUVN-I6107 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN-I6107 were studied both in rodent and non-rodent species. The effect of SUVN-I6107 on MK-801 (antagonist of the NMDA receptor) induced memory deficits in rats using object recognition task (ORT) and delay-induced social memory deficits in rats using social recognition task (SRT) was studied. Furthermore, effects of SUVN-I6107 on neuronal markers like soluble amyloid precursor protein (sAPPα) and inositol 1 phosphate (IP-1) levels were studied in rats. SUVN-I6107 showed allosteric potency at M1 receptor (EC of 355 nM) with improved neuronal firing, when tested in combination with EC of carbachol. SUVN-I6107 showed good oral bioavailability in rats, dogs, and monkeys. SUVN-I6107 was found to have brain penetration properties with adequate protein-free fraction. In a rat model, SUVN-I6107 has reversed the delay, scopolamine and MK-801 induced amnesias in ORT. SUVN-I6107 also significantly improved the memory in contextual fear conditioning task and SRT. Treatment with SUVN-I6107 produced significant increase in levels of cortical sAPPα and striatal IP-1 in rats. Results from the non-clinical studies suggest SUVN-I6107 may have memory enhancing property in various forms of dementias. SUVN-I6107 is currently being studied in a Phase-1 study (NCT06705088) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamic effects after single and repeated administrations in healthy human subjects.

Background SUVN‐I6107 is a novel and selective muscarinic M1 Positive Allosteric Modulator (PAM) being developed for the treatment of dementia due to neurodegenerative disorders. In the current research, the pharmacological properties of SUVN‐I6107 in various animal models of cognitive deficits were investigated. Methods SUVN‐I6107 was characterized using a calcium mobilization assay and the binding affinity towards the orthosteric M1 ‐ M5 site was investigated to assess the selectivity. The effect of SUVN‐I6107 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I6107 were studied both in rodent and non‐rodent species. The effect of SUVN‐I6107 on MK‐801 (antagonist of the NMDA receptor) induced memory deficits in rats using object recognition task (ORT) and delay‐induced social memory deficits in rats using social recognition task (SRT) was studied. Furthermore, effects of SUVN‐I6107 on neuronal markers like soluble amyloid precursor protein (sAPPα) and inositol 1 phosphate (IP‐1) levels were studied in rats. Results SUVN‐I6107 showed allosteric potency at M1 receptor (EC50 of 355 nM) with improved neuronal firing, when tested in combination with EC20 of carbachol. SUVN‐I6107 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I6107 was found to have brain penetration properties with adequate protein‐free fraction. In a rat model, SUVN‐I6107 has reversed the delay, scopolamine and MK‐801 induced amnesias in ORT. SUVN‐I6107 also significantly improved the memory in contextual fear conditioning task and SRT. Treatment with SUVN‐I6107 produced significant increase in levels of cortical sAPPα and striatal IP‐1 in rats. Conclusions Results from the non‐clinical studies suggest SUVN‐I6107 may have memory enhancing property in various forms of dementias. SUVN‐I6107 is currently being studied in a Phase‐1 study (NCT06705088) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamic effects after single and repeated administrations in healthy human subjects.

RationaleRopanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4β2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders.ObjectivesPharmacological and neurochemical characterization of Ropanicant to support a potential molecule for the treatment of depressive disorders.MethodsRopanicant was assessed for antidepressant-like activity using the rat forced swimming test (FST) and differential reinforcement of low rate −72 s (DRL-72 s). Alleviation of anhedonia was assessed in chronic mild stress model using sucrose preference test. To understand the mechanism of action, serotonin levels, ionized calcium-binding adaptor molecule 1 (Iba1), and brain-derived neurotrophic factor (BDNF) were determined. The onset of antidepressant-like activity was determined using the reduction in submissive behavior assay. The effects on cognition and sexual functions were assessed using the object recognition task and sexual dysfunction assay respectively. Interaction of Ropanicant, TC-5214, and methyllycaconitine (MLA) with citalopram was investigated individually in mice FST.ResultsRopanicant exhibited antidepressant like properties in the FST and DRL-72 s. A significant reduction in anhedonia was observed in the sucrose preference test. Oral administration of Ropanicant produced a significant increase in serotonin and BDNF levels, with a reduction in the Iba1 activity. The onset of antidepressant like effect with Ropanicant was within a week of treatment, and was devoid of cognitive dulling and sexual dysfunction. While Ropanicant potentiated the effect of citalopram in FST, such an effect was not observed with MLA or TC-5214.ConclusionsPreclinical studies with Ropanicant support the likelihood of its therapeutic utility in the treatment of depressive disorders.

Introduction SUVN-G3031, a potent histamine H3 receptor inverse agonist is being developed for the treatment of narcolepsy and other sleep related disorders. SUVN-G3031 has hKi of 8.7 nM at H3R with more than 100-fold selectivity against related GPCRs. SUVN-G3031 exhibited desired pharmacokinetic properties and brain penetration in preclinical species. SUVN-G3031 blocked R-α-methylhistamine induced water intake and increased tele-methylhistamine levels in brain and cerebrospinal fluid. Acute oral administration of SUVN-G3031 produced significant increase in acetylcholine, histamine, dopamine and norepinephrine levels in the cortex. SUVN-G3031 produced wake promoting effects in male Wistar rats and C57BL/6J mice. SUVN-G3031 was evaluated in Phase 1 clinical studies (US IND). It showed desirable pharmacokinetic profile with safety and tolerability in healthy human volunteers. Methods In the present study, effects of SUVN-G3031 on sleep/wake profile were evaluated in rats lesioned with neurotoxin orexin-2-saporin in lateral hypothalamus. EEG signals were acquired using telemetric device implanted intraperitoneally. Results Rats lesioned with orexin-2-saporin in lateral hypothalamus produced narcoleptic-like behavior. SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in rapid eye movement (REM) sleep in rats lesioned with orexin -2-saporin. Treatment with SUVN-G3031 decreased the DREM episodes indicative of anti-cataplectic effect in rodents. Conclusion Results from the current study provide a strong preclinical basis for potential of SUVN-G3031 in the treatment of sleep related disorders like narcolepsy with and without cataplexy. Phase 2 POC study for the treatment of narcolepsy is currently being planned in USA. Support (If Any) None