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Based on core symptoms of inattention and deficient impulse control, and the identification of effective pharmacotherapies such as amphetamine (AMP; Adderall

The 5-HT releaser/reuptake inhibitor fenfluramine has been recently reported to provide benefit as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, two types of severe childhood epilepsy. Despite its enhancement of 5-HT function, many effects of fenfluramine have been demonstrated to be dependent on 5-HT2C receptor activation, suggesting that 5-HT2C receptor activation may have an anticonvulsant property. The present study was designed to evaluate fenfluramine and 5-HT agonists of varying 5-HT2C agonist selectivity, the relatively nonselective mCPP and Ro 60-0175, and the selective 5-HT2C agonists lorcaserin and CP-809101 across a variety of acute seizure tests conducted in adult rats and mice, which have been instrumental in identifying the majority of clinically efficacious antiepileptic drugs. Tests included the maximal electroshock seizure (MES), MES threshold, and 6 Hz electrical convulsive seizure models and the chemoconvulsant pentylenetetrazole test. The effect of mCPP, lorcaserin, and CP-809101 against electrically evoked seizures in amygdala kindled rats was also investigated. Overall, at doses known to interact with 5-HT2CR, there was no clear class-related effect of these agonists in any test. The only notable antiseizure effect of fenfluramine was inhibition of MES-induced tonic seizures in the rat. The current preclinical studies using the classical acute seizure tests and an amygdala kindling model do not identify a reliable antiseizure effect of fenfluramine, an agent now used in the treatment of human epilepsies, including Dravet syndrome and Lennox-Gastaut syndrome. Given the nature of these epilepsies, early life and/or genetic models may have better construct validity and be more appropriate for further study.

Previous studies demonstrated that NMDA receptor antagonists such as dizocilpine (MK801) and the GluN2B NMDA antagonist Ro 63–1908 promote impulsive action (motor impulsivity). The effects of these treatments on impulsive choice and decision-making is less well characterized. Two experiments were undertaken. In the first experiment, given evidence for delay order as a factor in choice selection, the effect of dizocilpine was examined in a delay discounting task with separate groups of male Long-Evans rats trained to a schedule of either ascending (i.e. 0–40 s), or descending delays (i.e. 40–0 s). Under the ascending-delay schedule, dizocilpine (0.03–0.06 mg/kg SC) reduced discounting, yet on the descending-delay schedule discounting was increased. Subgrouping rats according to discounting rate under vehicle pretreatment were consistent with a treatment-induced choice perseveration. In a second experiment, male Long-Evans rats were trained to a gambling task (rGT). Neither dizocilpine (0.01–0.06 mg/kg SC) nor Ro 63–1908 (0.1–1 mg/kg SC) shifted choice from the advantageous to the disadvantageous options. However dizocilpine, and marginally Ro 63–1908, increased choice of the least risky, but suboptimal option. This effect was most evident in rats that initially preferred the disadvantageous options. Consistent with previous studies, both treatments increased measures of motor impulsivity. These results demonstrate that dizocilpine has effects on discounting dependent on delay order and likely reflective of perseveration. On the rGT task, neither dizocilpine nor Ro 63–1908 promoted risky choice, yet both NMDA receptor antagonists increased impulsive action.

Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by lorcaserin (0.3 mg/kg). Combining lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3 mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.

Amphetamine (AMP) and atomoxetine (ATX) represent two of the most widely studied drug treatments used in the investigation of impulsive behaviour. While both drugs have relatively well defined effects in tests designed to investigate impulsive action (e.g. 5-choice task; 5-CSRTT), the effects of both drugs in tests of impulsive choice (e.g. delay discounting) are less consistent. In the present study both AMP and ATX were tested in a rodent gambling task (rGT) and delay discounting in rats separately trained to either an ascending or descending delay schedule. Effects of both drugs were compared to measures of impulsive action (premature (PREM) responses) and perseverative (PSV) responses measured in the 5-choice and rGT tasks. Consistent with previous studies, AMP (0.1–1 mg/kg) increased both PREM and PSV responses, and ATX (0.5–2 mg/kg) reduced both measures in the 5-choice and rGT tasks. At equivalent doses ATX had no reliable effect on choice behaviour in either the rGT or delay discounting suggesting a null effect of this drug on impulsive choice and risky decision making. The effects of AMP were more complex, with a subtle shift in preference to a low risk (P1) choice in the rGT, and an effect on discounting that was unrelated to reinforcer value, but instead dependent on delay sequence and baseline choice preference. One aspect to these outcomes is to highlight the importance of multiple methodological factors when assessing drug effects on complex behaviours such as impulsive choice, and question what are the most appropriate test conditions under which to examine these drugs on discounting.

Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of fun...

NMDA GluN2B (NR2B) subtype selective antagonists are currently in clinical development for a variety of indications, including major depression. We previously reported the selective NMDA GluN2B antagonists Ro 63-1908 and traxoprodil, increase premature responding in a 5-choice serial reaction time task (5-CSRTT) suggesting an effect on impulsive action. The present studies extend these investigations to a Go-NoGo and delay discounting task, and the 5-CSRTT under test conditions of both regular (5s) and short (2-5s) multiple ITI (Intertrial interval). Dizocilpine was included for comparison. Both Ro 63-1908 (0.1-1mg/kg SC) and traxoprodil (0.3-3mg/kg SC) increased premature and perseverative responses in both 5-CSRT tasks and improved attention when tested under a short ITI test condition. Ro 63-1908 but not traxoprodil increased motor impulsivity (false alarms) in a Go-NoGo task. Dizocilpine (0.01-0.06mg/kg SC) affected both measures of motor impulsivity and marginally improved attention. In a delay discounting test of impulsive choice, both dizocilpine and Ro 63-1908 decreased impulsive choice (increased choice for the larger, delayed reward), while traxoprodil showed a similar trend. Motor stimulant effects were evident following Ro 63-1908, but not traxoprodil treatment - although no signs of motor stereotypy characteristic of dizocilpine (>0.1mg/kg) were noted. The findings of both NMDA GluN2B antagonists affecting measures of impulsive action and compulsive behavior may underpin emerging evidence to suggest glutamate signaling through the NMDA GluN2B receptor plays an important role in behavioural flexibility. The profiles between Ro 63-1908 and traxoprodil were not identical, perhaps suggesting differences between members of this drug class.

The 5-HT2C receptor agonist lorcaserin (Belviq®) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders. Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test. Lorcaserin (0.3–0.6 mg/kg SC) and CP-809101 (0.6–1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1–3 mg/kg SC) and CP-809101 (3–6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses. These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C receptor agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.

Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as ‘impulsive-compulsive disorders’. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06–0.6 mg/kg), CP-809101 (0.1–1 mg/kg) and atomoxetine (0.1–1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1–2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as ‘impulsive-compulsive disorders’. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

The 5-choice serial reaction time task (5-CSRTT) is employed extensively to measure attention in rodents. The assay involves animals trained to respond to a brief, unpredictable visual stimulus presented in one of five locations. The effects of experimental manipulations on response speed and choice accuracy are measured, and each related to attentional performance. The 5-CSRTT is also used to measure motor impulsivity. Adapted from a human task, the 5-CSRTT can be employed with rodents or primates, highlighting its translational value. Another strength of this procedure is its adaptability to task modification. An example is the 5-choice continuous performance task, which has both target and non-target trial types. Overall, the 5-CSRTT has proven to be valuable for drug discovery efforts aimed at identifying new agents for the treatment of central nervous system disorders and for further understanding the neurobiological processes of attention and impulsivity. Its flexibility offers considerable scope to the experimenter, and in this respect the task continues to evolve. © 2017 by John Wiley & Sons, Inc.

Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition.

Recently, an essential oil of selected quality produced from the flowering tops of Lavandula angustifolia Mill. by steam distillation (Silexan) has been approved in Germany for the treatment of restlessness in case of anxious mood. Based on the observed clinical effects, it has been speculated that lavender oil may exert benzodiazepine-like action including the known dependence and abuse potential of this class of drugs. Although no evidence for such an activity was generated during the long-standing medicinal use of lavender oil, further preclinical investigations were now conducted to evaluate this potential side effect in more detail. Twelve adult, male, Sprague-Dawley rats were trained to discriminate the benzodiazepine drug diazepam (2 mg/kg i.p.) from saline using a two-lever operant procedure. After approximately 40 training sessions the majority of rats learned the discrimination and pre-treatment with ascending doses of diazepam (0.3-2 mg/kg i.p.) produced a dose related generalization to the diazepam cue. In these same animals Silexan was administered to see if animals recognized the drug as "diazepam-like" i.e. generalized to diazepam or "saline-like". Silexan tested at doses 3-30 mg/kg i.p. produced almost exclusively (>90%) saline-like responding. Also there was no effect of Silexan on response rate, i.e. rate of lever pressing, at any dose suggesting that the test article is well tolerated and does not exert a sedating effect. In sum, Silexan has no diazepam-like interoceptive property in adult, male rats. This suggests that Silexan does not share the potential of benzodiazepines to induce the development of tolerance, dependence and addiction.

Selective 5-HT2C receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated. The primary aim was to evaluate the highly selective 5-HT2C agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-HT2C receptor agonists lorcaserin and Ro 60–0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials. CP-809101 (0.3–3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60–0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials. These studies support the utility of 5-HT2C agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-HT2C agonists.

The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT(2A) and 5-HT(2C) receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175 and the 5-HT(2A) receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT(2C) receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT(2C) and 5-HT(2A) receptors may be potential targets for therapies to treat some aspects of nicotine dependence.

Broad spectrum Anti-Epileptic Drugs (AED) are valued for their potential to treat refractory epilepsy and as general ‘neurostabilizers’ have been employed for a variety of neurological diseases including migrane, biopolar disorder and neuropathic pain. However, the benefits of historical AEDs have been constrained by unintended CNS side effects. Combining proprietary breakthrough chemistry with Fluorinov Pharma and NIH’s in vivo phenotypic screening strategy identified three completely novel candidate drugs, including FV-082 with superior safety and efficacy profiles. FV-082 was screened across available in vitro and rodent seizure models at ASP, and was found to display an excellent spectrum of anti-seizure activity and safety profiles superior to that produced by Depakote, Neurontin and Keppra. FV-082 has an oral ED50 of 20.1 ± 0.7 and 17.4 ± 0.6 mg/kg in the rat MES and mouse 6Hz (ip) assays, respectively. FV-082 prevented seizures induced by sound in the Audiogenic Seizure (AGS)-susceptible Frings mouse model (i.p) with an ED50 value of 13.0 ± 2.0 mg/kg. In addition, FV-082 displayed significant efficacy in the electrically induced corneally kindled mouse, kindled rat amygdala and hippocampal seizures models. Importantly, FV-082 was also found to limit seizure spread and elevate seizure threshold in preclinical animal models, therefore, it has the potential to be effective in refractory, or pharmacoresistant, epilepsy. Also, the anticonvulsant pharmacology suggests applicability for treating multiple forms of epilepsy, such as generalized tonic−clonic, complex partial, and myoclonic seizures, at dose levels that confer a favorable safety margin (therapeutic index ≥ 34). Safety assessment of FV-082 suggests no interaction with the major CYP isoenzymes when tested up to 500 μM and no functional hERG activity when tested up to 20 μM. Further, acute toxicity studies revealed that FV082 exhibited no adverse effects at oral and intravenous doses in rats and mice with a maximally tolerated dose greater than 600 mg/kg in the mice (i.p) and rats (p.o). Also, there was a pronounced safety margin between behavioral efficacy (rat oral MES neurotoxicity and (rat TD50 > 600 mg/kg) for a protective index (rat oral TD50/MES ED50) of >34-fold. Hence, FV-082 displays a considerably broader CNS therapeutic index superior to historical AEDs. Additionally, a convenient and cost effective manufacturing process for FV-082 has been developed allowing for access to multi-kilogram scale synthesis. In-vivo pharmacokinetic studies in rat and dog revealed that FV-082 had excellent oral bioavailability and good oral half-life, and excellent plasma drug levels across multiple models of epilepsy and pain. In addition, drug exposure as measured by Cmax and AUC was shown to be linear with dose. Mechanistically, broad ion channel profiling in combination with a CEREP broad profiling screen (10 μM) across 90 known GPCR, ion channel, transporter and enzyme targets studies suggest that several mechanisms contribute to the observed pharmacological profile of FV-082 but that no single mechanism is likely to be a major contributor. In fact, in whole-cell patch-clamp recordings FV-082 inhibited voltage-gated Na + channel Nav1.7, and the CEREP panel indicated that FV-082 interacted with androgen receptor (AR) and (h) recombinant enzyme monoamine-oxidase-B (MAO-B). The anticonvulsant profile of FV-082 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. Furthermore, in models of neuropathic pain (spinal nerve injury [SNI] and formalin inflammatory pain, administration of a single dose showed robust efficacy (SNI: 50 mg/kg ip; and formalin: 71 mg/kg ip). Based on these promising preclinical data, FV-082 warrants clinical investigation.

Broad spectrum Anti-Epileptic Drugs (AED) are valued for their potential to treat refractory epilepsy and as general ‘neurostabilizers’ have been employed for a variety of neurological diseases including migrane, biopolar disorder and neuropathic pain. However, the benefits of historical AEDs have been constrained by unintended CNS side effects of these non-selective medicines. Combining proprietary breakthrough chemistry with Fluorinov Pharma and NIH’s in vivo phenotypic screening strategy identified three completely novel candidate drugs, including FV-137 with superior safety and efficacy profiles targeting selective ion channels. FV-137 is a novel, orally administered AED, structurally distinct than any known AED, displaying promising preclinical efficacy and safety. FV-137 emerged from a program whose goal was to identify broad-spectrum anti-epileptic drugs (AED) using gold standard benchmarks such as Depakote ® , Neurontin ® and Keppra ® as primary comparators. FV-137 was extensively screened across all available in vitro and rodent seizure models at ASP, and was found to display an excellent spectrum of anti-seizure activity and safety profiles superior to that produced by Depakote, Neurontin and Keppra. FV-137 has an oral ED50 of 22.7 ± 0.6 and 104.9±4.3 mg/kg in the rat MES (po), mouse PTZ (ip) assays, respectively. FV-137 also produced a dose related protection of a psychomotor seizure syndrome induced by a 6-Hz electrical stimulus with an oral ED50 of 48.5 ± 1mg/kg, and prevented seizures induced by sound in the Audiogenic Seizure (AGS)-susceptible Frings mouse model (i.p) with an ED50 value of 28.9 ± 3.0 mg/kg. In addition, FV-137 displayed significant efficacy in the electrically induced corneally kindled mouse, kindled rat amygdala, kindled rat hippocampal and lamotrigineresistant kindled rat seizures models. Additionally, FV-137 also increased seizure threshold in a dose– dependent manner, therefore, it has the potential to be effective in refractory, or pharmacoresistant, epilepsy. In-vivo pharmacokinetic studies in rat revealed that FV-137 had excellent oral bioavailability (F% = 85%), moderate oral half-life (~3h), and predicted plasma drug levels in the range 5-50μM across multiple models of epilepsy. In addition, drug exposure as measured by Cmax and AUC was shown to be linear with dose. Safety assessment of FV-137 suggests no interaction with the major CYP isoenzymes when tested up to 500 μM, except for 1A2 and 2D6 with IC50 values of 19 uM and 156 uM respectively and no functional hERG activity when tested up to 50 μM. Irwin and acute toxicity studies suggest a maximally tolerated oral dose of greater than 500 mg/kg in the mice and rats. Mechanistically, in whole-cell patch-clamp recordings FV-137 inhibited P/Q-type Ca 2+ Channels, Cav2.1/β4/α2δ1 and Cav2.2/β3/α2δ1, and voltage-gated Na + channels, Nav1.6 and Nav1.7 and no inhibition up to 100 μM in other related ion channels. Importantly, no significant affinities were observed in a CEREP broad profiling screen (10 μM) across 90 known GPCR, ion channel, transporter and enzyme targets. The anticonvulsant profile of FV-137 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. Furthermore, in models of neuropathic pain (spinal nerve injury [SNI] and spinal nerve ligation models [SNL]) and formalin inflammatory pain, administration of a single dose showed robust efficacy (SNI: 23 mg/kg ip; SNL: 60mg/kg and formalin: 41 mg/kg ip). On the basis of its pharmacology and superior drug-like properties, FV-137 was identified as a promising AED candidate.

Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT(2C) receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.