RESUMO
BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.
Assuntos
Benzofuranos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/toxicidade , Estimulantes do Sistema Nervoso Central/síntese química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/toxicidade , Antagonistas de Receptores de GABA-A/síntese química , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/toxicidade , Antagonistas de Receptores de GABA-B/síntese química , Antagonistas de Receptores de GABA-B/química , Antagonistas de Receptores de GABA-B/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-A/química , Receptores de GABA-B/químicaRESUMO
BACKGROUND AND AIMS: In December 2006 the United States regulated sodium permanganate, a cocaine essential chemical. In March 2007 Mexico, the United States' primary source for methamphetamine, closed a chemical company accused of illicitly importing 60+ tons of pseudoephedrine, a methamphetamine precursor chemical. US cocaine availability and methamphetamine availability, respectively, decreased in association. This study tested whether the controls had impacts upon the numbers of US cocaine users and methamphetamine users. DESIGN: Auto-regressive integrated moving average (ARIMA) intervention time-series analysis. Comparison series-heroin and marijuana users-were used. SETTING: United States, 2002-14. PARTICIPANTS: The National Survey on Drug Use and Health (n = 723 283), a complex sample survey of the US civilian, non-institutionalized population. MEASUREMENTS: Estimates of the numbers of (1) past-year users and (2) past-month users were constructed for each calendar quarter from 2002 to 2014, providing each series with 52 time-periods. FINDINGS: Downward shifts in cocaine users started at the time of the cocaine regulation. Past-year and past-month cocaine users series levels decreased by approximately 1 946 271 (-32%) (P < 0.05) and 694 770 (-29%) (P < 0.01), respectively-no apparent recovery occurred through 2014. Downward shifts in methamphetamine users started at the time of the chemical company closure. Past-year and past-month methamphetamine series levels decreased by 494 440 (-35%) [P < 0.01; 95% confidence interval (CI) = -771 897, -216 982] and 277 380 (-45%) (P < 0.05; CI = -554 073, -686), respectively-partial recovery possibly occurred in 2013. The comparison series changed little at the intervention times. CONCLUSIONS: Essential/precursor chemical controls in the United States (2006) and Mexico (2007) were associated with large, extended (7+ years) reductions in cocaine users and methamphetamine users in the United States.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Transtornos Relacionados ao Uso de Cocaína/epidemiologia , Adolescente , Adulto , Idoso , Estimulantes do Sistema Nervoso Central/síntese química , Criança , Cocaína/síntese química , Inibidores da Captação de Dopamina/síntese química , Indústria Farmacêutica/legislação & jurisprudência , Controle de Medicamentos e Entorpecentes , Dependência de Heroína/epidemiologia , Humanos , Cooperação Internacional/legislação & jurisprudência , Legislação de Medicamentos , Metanfetamina/síntese química , México , Pessoa de Meia-Idade , Pseudoefedrina/provisão & distribuição , Compostos de Sódio/provisão & distribuição , Estados Unidos/epidemiologia , Adulto JovemRESUMO
AIMS: To help counter problems related to methamphetamine, Mexico has implemented interventions targeting pseudoephedrine and ephedrine, the precursor chemicals commonly used in the drug's synthesis. This study examines whether the interventions impacted methamphetamine treatment admissions-an indicator of methamphetamine consequences. DESIGN: Quasi-experiment: autoregressive integrated moving average (ARIMA)-based intervention time-series analysis. INTERVENTIONS: precursor chemical restrictions implemented beginning November 2005; major rogue precursor chemical company closed (including possibly the largest single drug-cash seizure in history) March 2007; precursor chemicals banned from Mexico (North America's first precursor ban) August 2008. SETTINGS: Mexico and Texas (1996-2008). MEASUREMENTS: Monthly treatment admissions for methamphetamine (intervention series) and cocaine, heroin and alcohol (quasi-control series). FINDINGS: The precursor restriction was associated with temporary methamphetamine admissions decreases of 12% in Mexico and 11% in Texas. The company closure was associated with decreases of 56% in Mexico and 48% in Texas; these decreases generally remained to the end of the study period. Neither intervention was associated with significant changes in the Mexico or Texas quasi-control series. The analysis of Mexico's ban was indeterminate due largely to a short post-ban series. CONCLUSIONS: This study, one of the first quasi-experimental analyses of an illicit-drug policy in Mexico, indicates that the country's precursor interventions were associated with positive impacts domestically and in one of the Unites States' most populous states--Texas. These interventions, coupled with previous US and Canadian interventions, amount to a new, relatively cohesive level of methamphetamine precursor control across North America's largest nations, raising the possibility that the impacts found here could continue for an extended period.