RESUMO
Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and ATP citrate lyase. This review shows that AACS is a highly regulated, cytosolic, and lipogenic enzyme and that many tissues can readily use KBs for denovo lipid synthesis. AACS has a low micromolar Km for acetoacetate, and supply of acetoacetate should not limit its activity in the fed state. In many tissues, AACS appears to be regulated in conjunction with the need for cholesterol, but in adipose tissue, it seems tied to fatty acid synthesis. KBs are readily utilized as substrates for lipid synthesis in lipogenic tissues, including liver, adipose tissue, lactating mammary gland, skin, intestinal mucosa, adrenals, and developing brain. In numerous studied cases, KBs served several-fold better than glucose as substrates for lipid synthesis, and when present, KBs suppressed the utilization of glucose for lipid synthesis. Here, it is hypothesized that a physiological role for the utilization of KBs for lipid synthesis is a metabolic process of lipid interconversion. Fatty acids are converted to KBs in liver, and then, the KBs are utilized to synthesize cholesterol and other long-chain fatty acids in liver and nonhepatic tissues. The conversion of fatty acids to cholesterol via the KBs may be a particularly important example of lipid interconversion. Utilizing KBs for lipid synthesis is glucose sparing and probably is important with low carbohydrate diets. Metabolic situations and tissues where this pathway may be important are discussed.
Assuntos
Acetoacetatos , Lactação , Feminino , Humanos , Acetoacetatos/metabolismo , Corpos Cetônicos/metabolismo , Ácidos Graxos , Fígado/metabolismo , Colesterol , GlucoseRESUMO
Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.
Assuntos
Propionatos/síntese química , Propionatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Meia-Vida , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Sphingosine-1-phosphate (S1P) receptor agonists are novel immunosuppressive agents. The selectivity of S1P1 against S1P3 is strongly correlated with lymphocyte sequestration and minimum acute toxicity and bradycardia. This study describes molecular modeling, site-directed mutagenesis, and affinity studies exploring the molecular basis for selectivity between S1P1 and S1P3 receptors. Computational models of human S1P1 and S1P3 receptors bound with two nonselective agonists or two S1P1-selective agonists were developed based on the X-ray crystal structure of bovine rhodopsin. The models predict that S1P1 Leu276 and S1P3 Phe263 contribute to the S1P1/S1P3 selectivity of the two S1P1-selective agonists. These residues were subjected to site-directed mutagenesis. The wild-type and mutant S1P receptors were expressed in Chinese hamster ovary cells and examined for their abilities to bind to and be activated by agonists in vitro. The results indicate that the mutations have minimal effects on the activities of the two nonselective agonists, although they have dramatic effects on the S1P1-selective agonists. These studies provide a fundamental understanding of how these two receptor-selective agonists bind to the S1P1 and S1P3 receptors, which should aid development of more selective S1P1 receptor agonists with immunosuppressive properties and improved safety profiles.
Assuntos
Imunossupressores/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Relação Estrutura-AtividadeRESUMO
A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
Assuntos
Imunossupressores/farmacologia , Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Ligantes , Contagem de Linfócitos/veterinária , Camundongos , Ratos , Transplante de Pele , Relação Estrutura-AtividadeRESUMO
A series of 2,5-cis-disubstituted pyrrolidines were synthesized and evaluated as S1P receptor agonists. Compounds 15-21 were identified with good selectivity over S1P3 which lowered circulating lymphocytes after oral administration in mice.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Pirrolidinas/química , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Ácidos Carboxílicos/síntese química , Estrutura Molecular , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
Assuntos
Acetatos/farmacologia , Pirrolidinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Acetatos/síntese química , Acetatos/química , Animais , Contagem de Linfócitos , Lisofosfolipídeos/antagonistas & inibidores , Camundongos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
Assuntos
Imunossupressores/síntese química , Oxidiazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Sobrevivência de Enxerto , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Contagem de Linfócitos , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Transplante de Pele , Relação Estrutura-AtividadeRESUMO
Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
Assuntos
Azetidinas/farmacologia , Imunossupressores/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Azetidinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imunossupressores/farmacocinética , Linfócitos/efeitos dos fármacos , Macaca mulatta , Camundongos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
The novel immunosuppressive agent FTY720 (1) is phosphorylated in vivo in a variety of species yielding an active metabolite that is an agonist of four of the five known G-protein-coupled sphingosine-1-phosphate (S1P) receptors. A synthesis amenable to producing gram quantities of the stereoisomeric phosphate esters, a determination of their absolute stereochemistry via an enantioselective synthesis and their characterization as S1P receptor agonists and antagonists is reported.
Assuntos
Imunossupressores/síntese química , Organofosfatos/síntese química , Propilenoglicóis/síntese química , Animais , Células CHO , Cricetinae , Cloridrato de Fingolimode , Humanos , Conformação Molecular , Esfingosina/análogos & derivadosRESUMO
A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Humanos , Conformação Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Relação Estrutura-AtividadeRESUMO
3-(N-Alkyl)aminopropylphosphonic acids are potent agonists of four of the five known sphingosine-1-phosphate (S1P) receptor subtypes.
Assuntos
Receptores Acoplados a Proteínas G/agonistas , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Humanos , Concentração Inibidora 50 , Ligantes , Organofosfonatos/síntese química , Compostos Organofosforados/síntese química , Radioisótopos de Fósforo , Relação Estrutura-AtividadeRESUMO
Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.
Assuntos
Compostos de Benzil/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Miocárdio/metabolismo , Compostos Organofosforados/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Animais , Compostos de Benzil/química , Sítios de Ligação , Células CHO , Cricetinae , Humanos , Concentração Inibidora 50 , Cinética , Lisofosfolipídeos/química , Lisofosfolipídeos/farmacologia , Camundongos , Compostos Organofosforados/química , Radioisótopos de Fósforo , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologiaRESUMO
Alteration in lymphocyte trafficking and prevention of graft rejection in rodents observed on exposure to FTY720 (1) or its corresponding phosphate ester 2 can be induced by the systemic administration of potent sphingosine-1-phosphate receptor agonists exemplified by 19. The similar S1P receptor profiles of 2 and 19 coupled with their comparable potency in vivo supports a connection between S1P receptor agonism and immunosuppressive efficacy.
Assuntos
Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Propilenoglicóis/administração & dosagem , Propilenoglicóis/química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Cloridrato de Fingolimode , Humanos , Fatores Imunológicos/metabolismo , Imunossupressores/administração & dosagem , Imunossupressores/química , Imunossupressores/metabolismo , Injeções Intravenosas , Masculino , Camundongos , Propilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivadosRESUMO
It has been reported recently that the phosphorylated form of the immunomodulator FTY720 activates sphingosine 1-phosphate G protein-coupled receptors. Therefore, understanding the biology of this new class of receptors will be important in clarifying the immunological function of bioactive lysosphingolipid ligands. The S1P(4) receptor has generated interest due to its lymphoid tissue distribution. While the S1P(4) receptor binds the prototypical ligand, S1P, a survey of other lysosphingolipids demonstrated that 4D-hydroxysphinganine 1-phosphate, more commonly known as phytosphingosine 1-phosphate (PhS1P), binds to S1P(4) with higher affinity. Using radiolabeled S1P (S133P), the affinity of PhS1P for the S1P(4) receptor is 1.6nM, while that of S1P is nearly 50-fold lower (119+/-20nM). Radiolabeled PhS1P proved to be superior to S133P in routine binding assays due to improved signal-to-noise ratio. The present study demonstrates the utility of a novel radiolabeled probe, PhS133P, for in vitro studies of the S1P(4) receptor pharmacology.
Assuntos
Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G , Proteínas de Saccharomyces cerevisiae , Esfingosina/análogos & derivados , Esfingosina/farmacocinética , Animais , Fatores de Transcrição de Zíper de Leucina Básica , Sítios de Ligação , Ligação Competitiva , Células CHO , Linhagem Celular , Membrana Celular/metabolismo , Cricetinae , Cinética , Ligantes , Radioisótopos de Fósforo , Receptores de Lisofosfolipídeos , Transativadores/metabolismo , Dedos de ZincoRESUMO
Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.