RESUMO
2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a â¼ 20-fold reduced affinity for human µ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 µM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.
Assuntos
Compostos de Bifenilo/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides kappa/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Comportamento Aditivo/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Compostos de Bifenilo/sangue , Compostos de Bifenilo/metabolismo , Condicionamento Psicológico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Extinção Psicológica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Terapia de Alvo Molecular , Atividade Motora/efeitos dos fármacos , Antagonistas de Entorpecentes/sangue , Antagonistas de Entorpecentes/metabolismo , Entorpecentes/sangue , Piperazinas/metabolismo , Prolactina/sangue , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Sulfonamidas/sangue , Sulfonamidas/metabolismoRESUMO
We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/fisiologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Inibidores de Fosfodiesterase/sangue , Inibidores de Fosfodiesterase/farmacocinética , Diester Fosfórico Hidrolases/genética , Ratos , Ratos Endogâmicos F344 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologiaRESUMO
A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.
Assuntos
Antineoplásicos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Oxazóis/síntese química , EstereoisomerismoRESUMO
[formula: see text] In this, the first of two letters, we outline our overall strategy for the total synthesis of phorboxazoles A (1) and B (2), rare oxazole-containing macrolides possessing extraordinary antimitotic activity, and describe the assembly of a C(3-19) subtarget (-)-5 for the total synthesis of phorboxazole A. The synthesis of (-)-5 was achieved in 15 linear steps (12% overall yield), exploiting a modification of the Petasis-Ferrier rearrangement to construct the C(11-15) cis-tetrahydropyran. Dimethylaluminum chloride (Me2AlCl) proved to be the Lewis acid of choice for the Petasis-Ferrier rearrangement.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Oxazóis/síntese química , Ácidos/química , OxirreduçãoRESUMO
[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis-Ferrier rearrangement of an E/Z mixture of trisubstituted enol ethers (15) to assemble the C(22-26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.