TRPV3 modulates nociceptive signaling through peripheral and supraspinal sites in rats.

TRPV3 is a nonselective cation channel activated by temperatures above 33°C and is reported to be localized in keratinocytes and nervous tissue. To investigate a role for TRPV3 in pain modulation, we conducted a series of in vivo electrophysiological studies on spinal and brain nociceptive neurons. Structurally diverse TRPV3 receptor antagonists reduced responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in neuropathic rats, but only CNS-penetrant antagonists decreased elevated spontaneous firing. Injections of an antagonist into the neuronal receptive field, into the L5 dorsal root ganglion, or intracerebroventricularly (ICV) attenuated the evoked firing, but only ICV injections reduced spontaneous activity. Intraspinal injections did not affect either. Spinal transection blocked the effect on spontaneous but not evoked firing after systemic delivery of a TRPV3 antagonist. Systemic administration of an antagonist to neuropathic rats also impacted the firing of On- and Off-cells in the rostral ventromedial medulla in a manner consistent with dampening nociceptive signaling. An assessment of nonevoked "pain," an EEG-measured pain-induced sleep disturbance induced by hind paw injections of CFA, was also improved with CNS-penetrant TRPV3 antagonists but not by an antagonist with poor CNS penetration. Antagonism of TRPV3 receptors modulates activity of key classes of neurons in the pain pathway in a manner consistent with limiting pathological nociceptive signaling and was mediated by receptors in the periphery and brain. Blockade of TRPV3 receptors is likely an effective means to alleviate mechanical allodynia and nonevoked pain. However, the latter will only be obtained by blocking supraspinal TRPV3 receptors.NEW & NOTEWORTHY Recent studies have linked TRPV3 to pain modulation, and much of this work has focused on its role in the skin-primary afferent interface. In this electrophysiological study, we demonstrate that receptor antagonists modulate evoked signals through peripheral mechanisms but blockade of supraspinal TRPV3 receptors contributes to dampening both evoked and nonevoked "pain" through descending modulation. Thus, the full therapeutic potential of TRPV3 antagonists may only be realized with the ability to access receptors in the brain.

Disturbances in slow-wave sleep are induced by models of bilateral inflammation, neuropathic, and postoperative pain, but not osteoarthritic pain in rats.

Preclinical assessment of pain has typically relied on measuring animal responses to evoked stimulation. Because of inherent limitations of these assays, there is a need to develop measures of animal pain/discomfort that are objective, not experimentally evoked, and mimic the human condition. Patients with chronic pain manifest a variety of co-morbidities, one of which is disturbances in sleep. We used electroencephalography to objectively assess 4 rat models of pain (inflammatory/complete Freund's adjuvant [CFA], neuropathic/chronic constriction injury [CCI], postoperative/skin incision, osteoarthritis/monosodium iodoacetate [MIA]) for the occurrence of sleep disturbances. Four different measures of slow-wave sleep (SWS) were examined: amplitude of 1- to 4-Hz waves, total time spent in SWS, time spent in SWS-1, and time spent in SWS-2. Bilateral injuries were more likely to induce a sleep disturbance than unilateral injuries in the CFA, CCI, and skin incision assays. Sleep disturbances occurred in the deeper stage of SWS, as the amplitude of 1- to 4-Hz waves and time spent in SWS-2 were significantly decreased in all models except the osteoarthritis model. Sleep disturbances lasted for approximately 3 to 14days, depending on the model, and were resolved despite continued hypersensitivity to evoked stimulation. Morphine, gabapentin, diclofenac, and ABT-102 (TRPV1 antagonist) all improved sleep in the bilateral CFA assay at doses that did not significantly alter SWS in uninjured rats. Preclinical assessment of compounds should follow the path of clinical studies and take into account diverse aspects of the "pain condition." This would include evaluating nociceptive thresholds as well as other endpoints, such as cognition and sleep, that may be affected by the pathological state.

Effects of the novel α7 nicotinic acetylcholine receptor agonist ABT-107 on sensory gating in DBA/2 mice: pharmacodynamic characterization.

Nicotinic acetylcholine receptor (nAChR) agonists improve sensory gating deficits in animal models and schizophrenic patients. The aim of this study was to determine whether the novel and selective α7 nAChR full agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107) improves sensory gating deficits in DBA/2 mice. Sensory gating was measured by recording hippocampal-evoked potential P20-N40 waves and determining gating test/conditioning (T/C) ratios in a paired auditory stimulus paradigm. ABT-107 at 0.1 µmol/kg (average plasma concentration of 1.1 ng/ml) significantly improved sensory gating by lowering T/C ratios during a 30-min period after administration in unanesthetized DBA/2 mice. ABT-107 at 1.0 µmol/kg was ineffective at 30 min after administration when average plasma levels were 13.5 ng/ml. However, the 1.0 µmol/kg dose was effective 180 min after administration when plasma concentration had fallen to 1.9 ng/ml. ABT-107 (0.1 µmol/kg) also improved sensory gating in anesthetized DBA/2 mice pretreated with α7 nAChR-desensitizing doses of nicotine (6.2 µmol/kg) or ABT-107 (0.1 µmol/kg) itself. Moreover, repeated b.i.d. dosing of ABT-107 (0.1 µmol/kg) was as efficacious as a single dose. The acute efficacy of ABT-107 (0.1 µmol/kg) was blocked by the nAChR antagonist methyllycaconitine, but not by the α4ß2 nAChR antagonist dihydro-ß-erythroidine. These studies demonstrate that ABT-107 improves sensory gating through the activation of nAChRs, and efficacy is sustained under conditions of repeated dosing or with prior nAChR activation with nicotine.

Pharmacological properties and procognitive effects of ABT-288, a potent and selective histamine H3 receptor antagonist.

Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.

Rats housed on corncob bedding show less slow-wave sleep.

Despite the reported advantages of corncob bedding, questions have emerged about how comfortable animals find this type of bedding as a resting surface. In this study, encephalography (EEG) was used to compare the effects of corncob and aspen-chip bedding on rat slow-wave sleep (SWS). According to a facility-wide initiative, rats that were weaned on aspen-chip bedding were switched to corncob bedding in home cages and EEG recording chambers. Spontaneous EEG recordings obtained for 5 wk after the switch to corncob bedding demonstrated that rats spent significantly less time in SWS as compared with levels measured on aspen chips just prior to the bedding switch. SWS remained low even after a 5-wk acclimation period to the corncob bedding. We then acutely switched back to aspen-chip bedding in EEG recording chambers. Acute reinstatement of aspen-chip bedding during EEG recording was associated with an average 22% increase in time spent in SWS, with overall levels of SWS comparable to the levels measured on aspen chips prior to the change to corncob bedding. Aspen-chip bedding subsequently was reinstated in both home cages and EEG recording chambers, and SWS baseline levels were restored. These data raise important concerns about the effects of corncob bedding on rodents used in research.

Treating the cognitive deficits of schizophrenia with alpha4beta2 neuronal nicotinic receptor agonists.

Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal alpha4beta2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the alpha4beta2 subtype in schizophrenia. For instance, studies in rodents show that alpha4beta2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that alpha4beta2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more alpha4beta2 selective compounds. It remains to be determined whether alpha4beta2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic alpha4beta2 subtype could be useful in improving cognitive function in schizophrenic patients.

Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor.

The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.

Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties.

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.

Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.

The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating.

RATIONALE: Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the alpha7 nicotinic acetylcholine receptor (nAChR) subtype. OBJECTIVE: The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent alpha4beta2 receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice. METHODS: Unanesthetized DBA/2 mice were treated either with nicotine, the alpha4beta2 antagonist dihydro-beta-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippocampal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios. RESULTS: Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-beta-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP. CONCLUSIONS: Activation of alpha4beta2 receptors by nicotine increases CAMP. However, under conditions where alpha4beta2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as alpha7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases.

Preclinical profiling and safety studies of ABT-769: a compound with potential for broad-spectrum antiepileptic activity.

PURPOSE: The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide]. METHODS: ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse. RESULTS: ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects. CONCLUSIONS: ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.

Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist.

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

Supraspinal and systemic administration of the nicotinic-cholinergic agonist (+/-)-epibatidine has inhibitory effects on C-fiber reflexes in the rat.

This study assessed the effects of the nicotinic agonist (+/-)-epibatidine (EPIB) on the C-fiber flexor reflex in the anesthetized rat. Electrical stimulation of the hindpaw produces a long latency (> 150 ms) C-fiber mediated electromyographic (EMG) burst in hindlimb flexor muscles. EPIB (0.01, 0.03 micromol/kg, i.p.) significantly reduced (p < 0.05) C-fiber -related EMG activity by 46 and 64%, respectively. This effect was similar to that produced by the opioid morphine (21.0 micromol/kg, i.p.) and the NMDA receptor antagonist MK-801 (3.0 micromol/kg, i.p.). Nicotinic receptor blockade with the antagonists mecamylamine (5.0 micromol/kg, i.p.) and chlorisondamine (23.0 nmol/rat, intracerebroventricular) attenuated the effects of systemic EPIB on the C-fiber reflex. EPIB injection (0.04 nmol/rat) into the nucleus raphe magnus significantly decreased C-fiber EMG activity by 67%, suggesting a supraspinal site of action. In contrast, EPIB (0.6 nmol/rat) administered into the lumbar spinal cord significantly increased the C-fiber reflex by 117%. In summary, systemic and supraspinal EPIB exerted an inhibitory effect on central pain transmitting pathways, while a stimulatory effect is elicited in the spinal cord. The inhibitory effects are consistent with the reported analgesic properties of EPIB. The excitatory effect may be related to the reported algogenic responses when EPIB is administered intrathecally.

The adenosine kinase inhibitor ABT-702 augments EEG slow waves in rats.

ABT-702 is a novel and selective non-nucleoside adenosine kinase (AK) inhibitor that produces increases in endogenous extracellular adenosine. Adenosine (ADO) is thought to be an important neuromodulator of sleep, therefore, the effects of ABT-702 and AK inhibition were examined on rat EEG and sleep, and compared to ADO receptor agonists to further evaluate the role of ADO receptor activation on sleep related EEG patterns. ABT-702 (10.0-30.0 micromol/kg, i.p.) increased the amplitude of the 1-4 Hz band (Fast Fourier Transform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 micromol/kg, i.p.), a centrally active, non-selective adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 micromol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 micromol/kg, i.p.), a peripherally active antagonist, did not, indicating that the EEG effects of ABT-702 are mediated by a central ADO receptor mechanism. The selective A(1) agonist N6-cyclopentyladenosine (CPA, 30.0 micromol/kg, i.p.) also increased the amplitude of 1-4 Hz band, but was not as efficacious as ABT-702. In contrast, the A(2A) agonist CGS-21680 (1.0-10.0 micromol/kg, i.p.) and the non-selective agonist, N(6)-ethylcarboximidoadenosine (NECA, 0.03-0.1 micromol/kg, ip.), lowered 1-4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 micromol/kg, i.p.) was found to significantly increase slow wave sleep and decrease REM sleep in rats implanted with both EEG and EMG electrodes for evaluation of sleep. These studies demonstrate that increased extracellular adenosine through AK inhibition can elicit modulatory effects on EEG slow waves via an interaction with central ADO receptor subtypes.

Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization.

Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3R antagonists or cognition-enhancing agents.