RESUMO
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
Assuntos
Compostos Benzidrílicos/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Sulfonas/química , Administração Oral , Animais , Compostos Benzidrílicos/agonistas , Compostos Benzidrílicos/farmacocinética , Estimulantes do Sistema Nervoso Central/agonistas , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacocinética , Agonismo Inverso de Drogas , Meia-Vida , Cinética , Modafinila , Ligação Proteica , Pirrolidinas/agonistas , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Sulfonas/agonistas , Sulfonas/farmacocinética , Vigília/efeitos dos fármacosRESUMO
OBJECTIVE: ABT-089, an α4ß2 neuronal nicotinic receptor partial agonist (generic name pozanicline), has demonstrated efficacy in adults with attention-deficit/hyperactivity disorder (ADHD) at doses of 40 mg once daily and 40 mg twice daily. The purpose of this exploratory pilot study was to obtain initial safety, tolerability, and efficacy data for an ABT-089 80-mg once-daily regimen to inform a decision of whether to include an 80-mg once-daily dose regimen in subsequent, definitive (phase 3) efficacy studies. METHOD: This phase 2, randomized, double-blind, parallel-group, placebo-controlled pilot study was conducted at 12 sites from March to August 2008. A screening/washout period of up to 4 weeks was followed by an 8-week double-blind treatment period. Eligible subjects met DSM-IV-TR criteria for ADHD and were randomized in a 1:1:1 ratio to ABT-089 40 mg once daily, ABT-089 80 mg once daily, or placebo. The primary efficacy variable was reduction from baseline to the final evaluation in the investigator-rated Conners' Adult ADHD Rating Scale for each active treatment group versus placebo. Safety assessments and pharmacokinetic sampling were also conducted. RESULTS: A total of 160 subjects were randomized, with 137 (86%) completing the trial. No statistically significant treatment effects were observed with either ABT-089 dose for any efficacy measures. The most commonly reported adverse events in the active treatment groups were nasopharyngitis (6.6%), upper respiratory tract infection (6.6%), and somnolence (5.7%). The incidence of adverse events did not differ significantly between active groups and placebo. There were no clinically significant laboratory, electrocardiogram, or physical examination findings. CONCLUSIONS: ABT-089 was generally well tolerated at doses up to 80 mg. Because ABT-089 is a weak partial neuronal nicotinic receptor agonist, the results may not predict the potential efficacy for other, more potent neuronal nicotinic receptor agonists. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00640185.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Agonismo Parcial de Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Piridinas/agonistas , Piridinas/farmacocinética , Pirrolidinas/agonistas , Pirrolidinas/farmacocinética , Receptores Nicotínicos/efeitos dos fármacosRESUMO
Spiradoline, an arylacetamide kappa (kappa) opioid receptor agonist, produced a potent tonic block of rat neuronal (EC(50)= 34+/-5 microM) and heart (EC(50)= 183+/-13 microM) sodium channels and also blocked IFMQ3 mutant neuronal sodium channels (EC(50)= 130+/-34 microM) that lack fast inactivation when expressed in Xenopus oocytes. Spiradoline produced a hyperpolarizing shift in the voltage-dependence of sodium channel inactivation and exhibited a marked frequency-dependent component to blockade of sodium channels. The onset of open channel block of the IFMQ3 channel by spiradoline was best fit with a first-order blocking scheme, yielding an affinity constant of 116 +/- 33 microM. Thus, spiradoline blocks sodium channels by interacting with the major states of the channel which could result in local anesthetic action in nerves and antiarrhythmic action in the heart.