Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.

Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 - a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Ki value of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naïve rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.

Comparison of enantiomers of SPFF, a novel beta2-Adrenoceptor agonist, in bronchodilating effect in guinea pigs.

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel beta2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta2-adrenoceptor selectivity. On the basis of this study, we compared the pharmacological properties of SPFF and its enantiomers ((-)-SPFF and (+)-SPFF) in guinea pigs taking isoprenaline or salbutamol (SAB) as referenced drugs. For the relaxation of both normal and precontracted trachea strips in vitro, (-)-SPFF was found more potent than (+/-)-SPFF or (+)-SPFF. Moreover, we confirmed that the bronchodilator effect of (-)- and (+)-enantiomers were due to activation of the beta2-adrenoceptor because this effect was antagonized by a specific beta2-adrenoceptor antagonist, ICI-118551, with similar pA2 values to those of (+/-)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to beta2-adrenoceptor was 6 and 164 fold greater than that of (+/-)- and (+)-SPFF, respectively. In addition, isomeric difference of overall selectivity between (-)-SPFF and (+)-SPFF was 10.7 fold for lung versus atria. (-)-SPFF displayed almost the same protective effect against bronchospasm induced by histamine-acetylcholine aerosol in conscious guinea pigs as (+/-)-SPFF did. However, the latent time of (+)-SPFF (1 mg.kg(-1)) was significantly shorter than that of (+/-)- and (-)-SPFF at the same doses. Finally, in the inhibition of histamine-induced increase of pulmonary resistance (RL) in anesthetized guinea pigs, (-)-SPFF was 1.3 and 3.5 times more potent than (+/-)- and (+)-SPFF. Correspondingly, in inhibiting the decrease of pulmonary compliance (CL) , the potencies of (-)- and (+)-enantiomers were approximately equivalent to that of (+/-)-SPFF. Furthermore, a study on the long-lasting action of the test drugs had shown that the effects of (-)-SPFF (30 microg.kg(-1)), (+/-)-SPFF (30 microg.kg(-1)) and (+)-SPFF (100 microg.kg(-1)) in inhibiting the increase of RL all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4 h after intraduodenal administration in inhibiting the decrease of CL. In conclusion, (-)-SPFF may be beneficial for the treatment of asthma because of its more potent efficacy and higher adrenoceptor affinity than (+/-)- or (+)-SPFF.

Soybean and ascorbate feeding in experimental carcinogenesis: immunological studies.

Soybean and/or sodium ascorbate have been demonstrated to have protective effects against carcinogenicity of the nitrosamine precursors dibutylamine and sodium nitrite in rats. Some immunological aspects of the cellular and humoral compartments of the immune system were investigated in this experimental model. The parameters chosen for the study were the lymphocyte transformation test, migration inhibition test, the demonstration of Fc and Fc plus complement receptors on the lymphocyte surface (EA and EAC rosette-forming test), and the determination of total serum proteins and their fractions. The results indicated that dibutylnitrosamine can be formed in vivo from its precursors dibutylamine and sodium nitrite, and that it affects the immune system of rats which showed an immunosuppressed state present as depressed cellular and humoral immunity. The protective role of soybean and/or ascorbate against carcinogenicity of dibutylamine and sodium nitrite was demonstrated by the absence of tumor formation. These agents were found to be capable of increasing the defense mechanism of rats by enhancing both cellular and humoral immunity in the presence of the carcinogenic nitrosamine precursors dibutylamine and sodium nitrite.