- Hyperpolarisation of Mirfentanil by SABRE in the Presence of Heroin
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Mirfentanil, a fentanyl derivative that is a μ-opioid partial agonist, is hyperpolarised via Signal Amplification By Reversible Exchange (SABRE), a para-hydrogen-based technique. [Ir(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene, C
- Robertson, Thomas B. R.,Gilbert, Nicolas,Sutcliffe, Oliver B.,Mewis, Ryan E.
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p. 1059 - 1064
(2021/05/17)
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- 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol- 2-one: A selective high-affinity antagonist for the human dopamine D4 receptor with excellent selectivity over ion channels
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After the requirement of pseudocycle formation in the ureas 3 and 7 for hD4 binding and selectivity was confirmed, structural hybridization with the known hD4 ligand 2 led to the design and identification of the lead 4-(2- oxo-1,3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD4 over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective 'four-step/one-pot' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD4 over hD2 and hD3. Greater selectivity (> 1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD4 over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD4 and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D4 receptor.
- Carling, Robert W.,Moore, Kevin W.,Moyes, Christopher R.,Jones, Elizabeth A.,Bonner, Katrine,Emms, Frances,Marwood, Rosemary,Patel, Shil,Patel, Smita,Fletcher, Alan E.,Beer, Margaret,Sohal, Bindi,Pike, Andrew,Leeson, Paul D.
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p. 2706 - 2715
(2007/10/03)
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- Nucleic acids encoding microsomal trigyceride transfer protein
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Nucleic acid sequences, particularly DNA sequences, coding for all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, expression vectors containing the DNA sequences, host cells containing the expression vectors, and methods utilizing these materials. The invention also concerns polypeptide molecules comprising all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, and methods for producing these polypeptide molecules. The invention additionally concerns novel methods for preventing, stabilizing or causing regression of atherosclerosis and therapeutic agents having such activity. The invention concerns further novel methods for lowering serum liquid levels and therapeutic agents having such activity.
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- Aromatic amides of heterocyclic compounds and therapeutic compositions containing same
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The invention relates to aromatic amides N-substituted by heterocyclic groups. More particularly, the invention relates to substituted benzoic acid amides of 1-arylalkylamino or aminoalkyl-N-heterocyclic rings and to pharmaceutical compositions thereof, which have the ability to antagonize the effects of dopamine or dopaminergic agents of endogenous or exogenous origin and which may be used for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, post operative conditions, etc., other gastrointestinal disorders such as dyspepsia, flatulence, bile regurgitations, hiatus hernia, peptic ulcer, reflux aerophagitis, gastritis, duodenitis, and cholethiasis, and a variety of conditions affecting the central nervous system such as acute and chronic psychoses, maniacal psychosis, schizophrenias, serious disturbances of behavior and non-melancholic depressive state and migraine.
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