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Three metabolites of N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline fumarate (SK-946), a novel central muscarinic cholinergic receptor agonist, were prepared to confirm their proposed structures, and tested for muscarinic receptor affinity in vitro.
From the ethyl acetate soluble fraction of twigs of Magnolia denudata (Magnoliaceae), seven new neolignan derivatives, 1-7, were isolated along with eighteen known lignan and neolignan derivatives, 8-25. The structures of the new neolignans were elucidated by means of spectral methods, especially by 1H-NMR and 13C-NMR spectra, and two dimensional NMR methods such as 1H-detected heteronuculear multiple bond connectivity1 (HMBC), 1H-detected multiple quantum coherence (HMQC) and 1H-1H-correlation spectroscopy (COSY). Compounds 1-4 have novel structures possessing a 6-oxabicyclo[3.2.2]nonane skeleton and compounds 5-8 also have novel structures possessing a bicyclo[3.2.1]octane skeleton. The anti-platelet-activating factor (PAF) activity of these compounds was tested by measurement of inhibition activity against acetyl transferase to lyso-PAF.
PURPOSE: To report our experience with perfluoro-N-octane (PFO) in the surgical management of complicated retinal detachments due to proliferative diabetic retinopathy. METHODS: Retrospective review of 18 consecutive eyes of 18 patients with tractional or combined tractional and rhegmatogenous retinal detachments due to severe proliferative diabetic retinopathy managed by pars plana vitrectomy and the intraoperative use of PFO. Preoperative characteristics, intraoperative findings and procedures and postoperative results were recorded. RESULTS: The mean preoperative acuity was 2/200 (range, 20/25 to light perception). The mean final visual acuity was 4/200 (range, 20/20 to no light perception). With a mean follow-up of 6 months, there was an 89% anatomic reattachment rate at the last visit and visual acuity was stable or improved in 72% of eyes. CONCLUSIONS: In our experience, PFO is a helpful surgical adjunct in the anatomic reattachment of tractional or combined tractional and rhegmatogenous diabetic retinal detachments. Visual acuity was stabilized or improved in the majority of eyes.
A procedure was proposed allowing one to synthesize RNA mimics on the basis of conjugates of diazabicyclo[2.2.2]octane with imidazole bearing a varying number of positive charges (nDm series, where n is the number of positive charges at neutral pH, m is the code of an imidazole-containing fragment of the catalytic domain: 1, histamine; 2, histidine methyl ester). The hydrolytic activity of six compounds of this series was studied under physiological conditions using in vitro transcript of human mitochondrial tRNA(Lys) as a substrate. It was shown that the rate of RNA hydrolysis with nDm conjugates rises with an increase in the number of positive charges: an approximately 30-fold acceleration of hydrolysis was observed with an increase in the total charge of the construct from +2 to +4.
The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2.3-dicarboximide with an expected anxiolytic activity.
The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2.3-dicarboximide with an expected anxiolytic activity.
The preparation of a number of derivatives of N-hydroxy-1,4-dimethyl-dibenzo[e.h]bicyclo[2.2.2]octane-2,3dicarboximide with a potential activity on central nervous system has been described.
The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane -2.3-dicarboximide with an expected anxiolytic activity.
On the basis of imidazole and bisquaternary salts of 1,4-diazabicyclo[2.2.2]octane, a number of highly effective catalysts of the nDm series (here, n is the number of positive charges at neutral pH values and m is the digital code of the catalytically active fragment: 1, histamine, and 2, histidine methyl ester) were synthesized for the cleavage of the phosphodiester bonds in ribonucleic acids. A general method for the synthesis of chemical ribonucleases was suggested, which helps vary both the number of positive charges in their RNA-binding domain and the catalytic center. By the example of hydrolysis under physiological conditions of the in vitro transcript of tRNA(Lys) from human mitochondria, it was shown that the RNA cleavage rate with the nDm conjugates increases approximately 30-fold along with the increase in the number of positive charges from two to four.
The preparation is described of a number of new N-substituted derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2,3-dicarboximide with potential anxiolytic activity.
Bioisosteric replacement of the 9-azabicyclo[4.2.1]nonane pharmacophoric element of the novel alkaloidal marine toxine pinnamine (5) by the 8-azabicyclo[3.2.1]octane moiety resulted in conformationally restricted analogues 6a and 6c of (-)-ferruginine (4). Key step in the diastereoselective synthesis of these pyranotropanes was the condensation of enantiopure ecgonine methyl ester (9) from the "chiral pool" with the lithium anion of N-tert-butylbutyraldimin and subsequent cyclisation with TFA. The potential nAChR ligands were tested for their in vitro affinity for the (alpha4)2(beta2)3 and the alpha7* nAChR subtypes. Despite obvious structural similarities with the potent alkaloids pinnamine (5) and (-)-ferruginine (4) the pyranotropanes 6a and 6c exhibited distinctly lower nAChR affinities.
Electron transport activity of beet spinach thylakoids was enhanced in the presence of aliphatic amine, DABCO (1,4-diazobicyclo (2,2,2) octane), a hydrophilic proton trapping agent. The extent of stimulation was pH-dependent and similar to the effect of the uncoupler ammonium chloride on electron transport. The stimulation of whole-chain (H2O-->MV) electron transport activity was observed only at high (rate-saturating) light intensity. The light-induced proton uptake coupled to electron transport of thylakoid was also arrested by DABCO, suggesting that DABCO uncouples thylakoid phosphorylation by proton trapping.
The metabolism of 8-methyl-8-azabicyclo- 3,2,1]octan-3-yl 3,5-dichlorobenzoate (MDL 72,222) was studied in the dog and monkey. Four urinary metabolites were detected by HPLC, HPLC/MS, and GC/MS, and were identified by comparison to authentic standards. The major metabolite in the dog, approximately 41% of the administered dose excreted between 0 and 120 hr, was the MDL 72,222-N-oxide. On the other hand, the major metabolite in the monkey was the glycine conjugate of 3,5-dichlorobenzoic acid (greater than 56% of the dose). Seven percent of the dose in the monkey urine was free 3,5-dichlorobenzoic acid. N-Desmethyl MDL 72,222 was present at 2.5 and 1% in the dog and monkey, respectively. Very little (less than 1%) of the parent compound was found in urine. The major pathways of metabolism of MDL 72,222 are N-oxidation, N-demethylation, ester hydrolysis, and amino acid conjugation.
The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2.3-dicarboximide with an expected anxiolytic activity.
Perfluoro-N-octane (PFO) is a heavy liquid that is used as an aid for complicated retinal surgical procedures. Although PFO is usually removed intraoperatively, the radiographic appearance of retained PFO may mimic an intraocular foreign body or vitreous hemorrhage. As the use of PFO in retinal procedures has become more widespread, recognition of its imaging appearance has become important in the differential diagnosis of intraocular foreign body and ocular trauma.
The synthesis of a series of N-substituted O-(3-amino-2-hydroxypropyl)oximes of 1,3,3-trimethyl-5-endo-(1-piperidinyl or 4-morpholinyl)-2-oxabicyclo [2.2.2]octan-6-ones is described. Some of these ethers showed strong local anesthetic activity in mice and platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid, as well as moderate hypotensive, antiarrhythmic and analgesic activities in rats and mice.
Regulation of the supramolecular structure and catalytic activity of the heterodimeric enzyme gamma-glutamyltransferase in the system of Aerosol OT reversed micelles in octane was studied. Variation of the hydration degree causes a reversible dissociation of the enzyme to the light and heavy subunits, both possessing the catalytic activity. The subunits were separated on the preparative scale in the reversed micelle system using ultracentrifugation. The active centres of gamma-glutamyltransferase were studied using the enzyme's irreversible inhibitor AT-125 (L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid). It is shown that the separation of the gamma-glutamyltransferase subunits results in "opening" of a new active centre in the heavy subunit, whereas in the enzyme's dimeric form this centre is masked and not accessible to the inhibitor's molecule. The kinetic and inhibitor analysis data indicate that the active centres in the light and heavy subunits are similar.
Low viscosity perfluorocarbon liquids are useful adjuncts during vitreoretinal surgery. This study evaluates perfluoro-n-octane (PFnO) for intraoperative use by examining ocular tolerance in rabbits and pigs. Rabbits were treated with intravitreal placement of PFnO for 48 hours and were examined during a period of 2 months following treatment. No clinical, electroretinographic, or light and electron microscopic evidence of adverse effects on the retina were observed. Small residual amounts of PFnO produced no adverse histologic changes 6 months after treatment. In pigs treated with mechanical vitrectomy and placement of PFnO for 3 hours, electron microscopic evaluation of the retina confirmed that the liquid had been well tolerated. These findings indicate that PFnO is safe for intraoperative use. When PFnO remained in the vitreous cavity of rabbits for longer than 1 week, varying degrees of globule dispersion occurred. Furthermore, histologic examination revealed changes in the inferior retina: photoreceptor outer segments were distorted, the outer plexiform layer was narrowed, and preretinal accumulation of macrophages had occurred.