ABSTRACT
The present study aimed at defining the best scheme of administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive modulator (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986) [once daily (o.d.) administration of 1 mg/kg for 3 days vs. three times daily (t.i.d.) administration of 0.3 mg/kg for 3 days] to get an optimal procognitive activity in the object recognition task in rats. Memory performance [Recognition Index (RI)] of rats was significantly improved 1 h (RI = 41%, P < 0.01) and 3 h (RI = 46%, P < 0.001) following oral administration of S 18986 (1 mg/kg, o.d.) when compared with animals receiving the vehicle (RI = 6%). When the interval between administration and testing was increased to 6 h and 9 h, no statistically significant improvement in memory performance was observed (RI = 42% for 6 h and RI = 18% for 9 h vs. 20% for the vehicle group). When S 18986 was administered at 0.3 mg/kg t.i.d., no statistically significant improvement in memory performance was observed (RI = 36%). These findings show a long-lasting efficacy of the AMPA receptor allosteric modulator in the object recognition task despite a short half-life in plasma and in brain (approximately 1 h). Accordingly, multiple administrations of S 18986 are not required to obtain a maximal efficacy in this paradigm, because a o.d. schedule of administration leads to a powerful procognitive activity.
Subject(s)
Benzothiadiazines/administration & dosage , Benzothiadiazines/pharmacology , Exploratory Behavior/drug effects , Memory/drug effects , Nootropic Agents/administration & dosage , Nootropic Agents/pharmacology , Receptors, AMPA/drug effects , Allosteric Regulation , Animals , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Histamine H3 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 H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 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 ED50 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.
