Histamine H 3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H 3 receptor. On the stimulation of guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ϳ50% higher than that of ciproxifan. Its in vitro potency was ϳ6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED 50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.The cerebral histaminergic neurons seem to play a critical role in the maintenance of wakefulness and higher cerebral functions, e.g., attention or learning (for review, see Schwartz et al., 1991;Haas and Panula, 2003). Hence, druginduced activation of histaminergic neurotransmission in the central nervous system represents a promising therapeutic target in a large variety of neuropsychiatric disorders in which these functions are compromised and for which available therapeutic opportunities are limited in this respect .Stimulation of postsynaptic H 1 and/or H 2 receptors by agonists is, however, not acceptable due to unavoidable and detrimental actions of these drugs at peripheral, i.e., mainly cardiovascular and gastric targets. In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al., Article, publication date, and citation information can be found at

BF2.649, a high affinity and selective non-imidazole histamine H 3 -receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C max or AUC values. At low oral doses (2.5-20 mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation.DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons.BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition.These observations suggest that H 3 -receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.

The effects of the Ito blocker, tedisamil (0.1, 1.0, and 3.0 mg/kg, IV), and the IK blocker, E-4031 (0.1, 1.0, and 3.0 mg/kg, IV), on the incidence and duration of reperfusion-induced arrhythmias were compared in the anesthetized rat (n = 12 per group). Reperfusion arrhythmias were evaluated after a 5 minute occlusion period of the left main coronary artery. In the absence of any pronounced effect on blood pressure, tedisamil and E-4031 reduced heart rate in a dose-dependent manner. During the preischemic period, QTc interval was increased by tedisamil but was not changed by E-4031. Both compounds increased the QTc interval during the ischemic period and also during the reperfusion. E-4031 was unable to reduce the incidence and duration of reperfusion-induced ventricular arrhythmias after 5 minutes of coronary artery occlusion. Tedisamil dose-dependently reduced the duration of reperfusion arrhythmias and their incidence. In a second set of experiments, the combination of tedisamil (1.0 mg/kg) with E-4031 (1.0 mg/kg) was administered. The electrocardiographic action of this combination was similar to that observed with tedisamil given alone. However, with the combination the incidence of fibrillation was reduced from 83% in the control group to 8% in the treated group (p < 0.001), and the mortality was reduced from 67% to 0% (p < 0.001), that is, to a greater extent than with tedisamil (1.0 mg/kg) alone. The results show that the blockade of Ito by tedisamil allows a reduction of reperfusion-induced mortality and that a specific IK blocker (E-4031) is devoid of antifibrillatory action in the anesthetized rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Background and PurposeWe evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.Experimental ApproachNonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro‐arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell‐derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B‐recommended assays included in vitro hERG (KV11.1) channels, in vivo dog studies with follow‐up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro‐arrhythmia model.Key ResultsBoth sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT‐liability or pro‐arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late INa reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide‐induced early after‐depolarizations (EADs) in the ICH S7B studies. Studies in stem cell‐derived human cardiomyocytes with dofetilide or E‐4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell‐derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies.Conclusions and ImplicationsOur findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro‐arrhythmia models when the results from CiPA studies are ambiguous.

The effects of the specific bradycardic agent, zatebradine (UL·FS 49), on ventricular arrhythmias occurring during an acute ischemia were compared to those of verapamil. Anesthetized rabbits were submitted to a ligation of the left circumflex coronary artery for 20 min. Zatebradine (150 and 750 µg/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dt_max. In comparison, verapamil (150 and 750 µg/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dt_max. The incidence of ventricular premature beats occurring during acute ischemia was changed neither by zatebradine nor by verapamil. Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 µg/kg of zatebradine and 0% with verapamil (750 µg/kg, p < 0.05). The action of zatebradine on ischemia-induced ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both zatebradine and verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both zatebradine and verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by verapamil and increased by zatebradine showing that at the concentrations used, zatebradine did not exhibit any calcium antagonistic activity when compared to verapamil. The results of the present study suggest that the specific bradycardic agent zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhythmias.