RESUMEN
With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Benzoxazinas/farmacología , Inhibidores de la Colinesterasa/farmacología , Piperazinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Benzoxazinas/síntesis química , Benzoxazinas/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Donepezilo , Diseño de Fármacos , Humanos , Indanos/farmacología , Simulación del Acoplamiento Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/farmacología , Unión Proteica , Relación Estructura-ActividadRESUMEN
A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT1A R (Ki = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (Ki = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Simulación del Acoplamiento Molecular , Receptor de Serotonina 5-HT1A/metabolismo , Serotoninérgicos/síntesis química , Serotoninérgicos/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Antidepresivos/síntesis química , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Estructura Molecular , Serotoninérgicos/química , Relación Estructura-ActividadRESUMEN
A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-h) was synthesized and evaluated for binding affinity at the human 5-hydroxytryptamine(1A) receptor (5-HT(1A)R) compounds (12b) and (12h) showed the highest 5-HT(1A) receptor affinity (IC(50)=15 nM). Molecular docking studies with all the compounds in a homology model of 5-HT(1A) showed that the main interaction anchoring the ligand in the receptor was a charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate(3.32).
Asunto(s)
Indoles/química , Piperazinas/química , Receptor de Serotonina 5-HT1A/química , Ácido Aspártico/química , Sitios de Unión , Simulación por Computador , Humanos , Indoles/síntesis química , Piperazina , Estructura Terciaria de Proteína , Receptor de Serotonina 5-HT1A/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a-f, 7a-f and their corresponding alcohols 8a-f were synthesized and evaluated for their affinity towards 5-HT(1A) receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (K(i) = 2.30 µM) toward 5-HT(1A) sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Piperazinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
BACKGROUND: There are no internationally validated questionnaires to investigate the prevalence of infant wheezing. This study was undertaken to validate a questionnaire for the International Study on the Prevalence of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). MATERIAL AND METHODS: Construct and criterion validity were tested for the question 'Has your baby had wheezing or whistling in the chest during his/her first 12 months of life?'. Construct validity (i.e. the ability of parents and doctors to refer to the same symptoms with the same words) was tested in a sample of 50 wheezing and 50 non-wheezy infants 12-15 months of age in each of 10 centres from 6 different Spanish- or Portuguese-speaking countries. Criterion validity (i.e. the ability of parents to correctly detect the symptom in the general population) was evaluated in 2 samples (Santiago, Chile and Cartagena, Spain) of 50 wheezing and 50 non-wheezing infants (according to parents) of the same age, randomly selected from the general population, who were later blindly diagnosed by a paediatric pulmonologist. RESULTS: Construct validity was very high (kappa test: 0.98-1) in all centres. According to Youden's index, criterion validity was good both in Cartagena (75.5%) and in Santiago (67.0%). Adding questions about asthma medication did not improve diagnosis accuracy. CONCLUSIONS: The EISL questionnaire significantly distinguished wheezy infants from healthy ones. This questionnaire has a strong validity and can be employed in large international multicentre studies on wheezing during infancy.