The base-exchange enzymes which catalyze exchange of free serine, choline, and ethanolamine with polar head groups of phospholipids are known to occur in eukaryotic cells. To understand the physiological roles of the base-exchange reactions, a rapid autoradiographic in situ enzyme assay has been developed for detecting the base-exchange activities in Chinese hamster ovary (CHO) cell colonies immobilized on filter paper or polyester cloth and obtained several mutants strikingly defective in the choline-exchange activity. CHO cell mutants that required exogenously added phosphatidylserine for cell growth were also isolated by using the replica technique with polyester cloth. Biochemical characterization of these mutants has revealed the following results. 1) There are at least two kinds of serine-exhange enzyme in CHO-K1 cells ; one of the enzymes (serine-exchange enzyme I) can catalyze the base-exchange reaction of phospholipids with serine, choline and ethanolamine, and the other enzyme (serine-exchange enzyme II) does not use choline as a substrate. 2) Phosphatidylserine in CHO cells is biosynthesized through the following sequential reactions : phosphatidylcholine→phosphatidylserine→phosphatidylethanolamine→phsophatidylserine. The three reactions are catalyzed by serine-exchange I, phosphatidylserine decarboxylase, and serine-exchange enzyme II, respectively. 3) Serine-exchange enzyme I is essential for the growth of CHO cells. In addition, we have found that exogenous phosphatidylserine can be efficiently incorporated into CHO cells and utilized for membrane biogenesis, endogenous phosphatidylserine biosynthesis thereby being suppressed.
Phencyclidine (PCP) is a major drug of abuse in the United States. It is a particularly interesting pharmacological tool because it induces psychosis (known as PCP-induced psychosis) in man, which has been diagnosed initially as schizophrenia, and also induces amnesia. In the present review, recent results of experiments with PCP are discussed. The presence of an endogenous ligand for PCP receptors has been strongly suggested since the presence of highly specific and selective binding sites for PCP in the brain has been discovered. The endogenous factors that inhibit the binding of [3H] PCP and produce PCP-like pharmacological activity have been isolated from porcine, bovine and guinea-pig brains. PCP and sigma opioids may act through the same binding sites, since the psychotomimetic benzomorphans, classed as sigma opioids, inhibit binding of [3H] PCP and show PCP-like actions in several behavioral assays. However, recent works by a number of investigators indicate that PCP binding sites and sigma opioid sites may be distinct due to differences in drug selectivity and regional distribution. Metaphit, a derivative of PCP has been synthesized and identified as a rapid and specific site-directed acylating agent of PCP receptors in rat brain. The antagonistic effect of PCP on excitation of central mammalian neurons by N-methyl-D-aspartate (NMDA) and the function of NMDA receptors associated with learning and memory mechanisms have been reviewed. We have attempted to develop an animal model for the negative symptoms of schizophrenia since there is no animal model although many patients have exhibited negative symptoms. We have proposed that PCP-induced head-twitch, head-weaving and immobilization can be used as the model of negative symptoms.
Poly (γ-methyl L-glutamate) (PMLG) was mixed with one of the lipids, such as L-α-dilauroylphosphatidylcholine, L-α-distearoylphosphatidylcholine, egg yolk lecithin, trilaurin, cholesterol and cholesterylacetate, and spread at air-water interface as insoluble monolayers. The surface pressure-mean area curves were obtained. Three transitions were observed in the mixed monolayers. These were the collapse of lipid monolayer, the bilayer formation from polymer monolayer and the formation of duplex film. Neither the collapse pressures of the lipids nor the bilayer formation pressure of PMLG changed with compositions, indicating that PMLG and lipids were practically immiscible in the monolayers. The formation pressures of the duplex films mainly depended on the kind of polar groups of lipids. By considering the work of adhesion of the polymer to the polar groups of the lipids, it was concluded that PMLG molecules in the duplex films are situated under the lipid monolayers.
Poly (γ-methyl L-glutamate) (PMLG) was added to mixtures of triolein (TO) and L-α-dilauroylphosphatidylcholine (DLPC). The mixtures were spread as insoluble monolayers at an air-water interface. PMLG caused phase separation in the monolayers and formed duplex films where PMLG was situated under polar groups of the lipid monolayers. In the mixed monolayers four transitions (a collapse of the lipid monolayer, a bilayer formation from PMLG monolayer, a formation of the duplex film and a transition of the duplex film) were observed and multiphases equilibria were found. From collapse pressures of lipid monolayers and formation pressures of the duplex films, lipid compositions in the lipid phases were estimated, and it was found that an increase in PMLG amount resulted in a decrease in TO concentration in the lipid phase being in equilibrium with the polymer phase or the duplex film. It was shown that PMLG caused unequal distribution of the lipids in the mixed monolayers.
The constituents of four ferns of the genus Plagiogyria were investigated. The ferns and isolated compounds are as follows. P. formosana : plagiogyrin A (2), fern-9 (11)-ene (4), 21αH-fern-9 (11)-ene (5), fern-9 (11)-en-12-one (6), hydroxyhopane (7), hydroxyisohopane (8), dryocrassol (9), dryocrassyl acetate (10), methyl hopan-30-oate (11), 17, 21-epoxyhopane (15), hop-17 (21)-ene ozonide A (16), hopene-II (17), ferna-7, 9 (11)-diene (18). P. adnata : 2. P. dunnii : 2, plagiogyrin B (3). P. stenoptera : 2. As plagiogyrin A and its derivatives have been isolated from two other ferns of the same genus, P. euphlebia and P. matsumureana, they may be considered as chemical markers of this genus.
A series of N-(pyrido [2, 3-d] pyrimidine-6-carbonyl) ampicillin and -amoxicillin derivatives (1-3) were synthesized and tested for antibacterial activity and acute toxicity in mice. 5, 8-Dihydro-2-(1-piperazinyl)-5-oxopyrido [2, 3-d] pyrimidine-6-carboxylic acid (7) was converted to N-acyl- and -alkylpiperazinyl derivatives (8 and 9) by acylation and alkylation, respectively ; a part of 9 was alternatively prepared by the reactions involving the displacement of N-alkylpiperazines with sulfoxide 11 which was derived from ethyl 5, 8-dihydro-2-methylthio-5-oxopyrido [2, 3-d] pyrimidine-6-carboxylate (10). Treatment of 4, 5, 8 and 9 with ethyl chloroformate followed by the reaction with ampicillin and amoxicillin gave the desired N-acylampicillin (2) and -amoxicillins (1 and 3), respectively. Among compounds 1-3, sodium 6-[D-(-)-2-(2-(4-formyl-1-piperazinyl)-5, 8-dihydro-5-oxopyrido [2, 3-d] pyrimidine-6-carboxamido)-p-hydroxyphenylacetamido] penicillanate (3l, PL-385) was found to be the most excellent in antibacterial activity and to be the less potent in acute toxicity in mice. An alternative route for the synthesis of PL-385 was accomplished, consisting of the reaction of an active ester 13 with amoxicillin. Structure-activity relationships of 1-3 were discussed.
A series of N-alkylampicillin (2), N-heteroarylampicillin (5) and N-heteroarylcephalexin (6) were synthesized in order to obtain β-lactam detivatives with a broad and orallypotent antibacterial activity similar to that of the injectable N-acylampicillins. 6-[2-[(Pyrido [2, 3-d] pyrimidin-6-yl) methylamino]-2-phenylacetamido] penicillanic acid derivatives (2) were prepared by the reduction of the Schiff base which was derived from the reaction of pyrido [2, 3-d] pyrimidine-6-carboxaldehyde (1) with ampicillin. 6-N-(4-Pyrimidinyl) ampicillin and -cephalexin derivatives (5 and 6) were obtained by the reaction of 4-chloropyrimidine (4) with ampicillin or cephalexin. Compounds 2, 5 and 6 were tested in vitro antibacterial activity and, however, none of them have a broad and potent activity.
The effect of benzyl nicotinate (NB) and/or lecithin (PC) on the absorption of indomethacin (IM) through rat back skin were studied by using the 14C-IM gel ointment preparations containing 0.5%NB and/or 2%PC. The absorption of IM estimated from the amount remained both on the plaster and on the surface of skin was increased slightly by NB or PC and significantly by the combination of NB and PC. The radioactivity excreted in the urine and feces was much higher in the preparations containing PC than control 120h after a topical application for 7h. Comparing with the pharmacokinetic parameters of IM from control, those from the preparation containing PC were significantly affected ; plasma AUC was higher, MRT was shorter, and VRT was larger. NB was fastly absorbed and disappeared from skin, but the disappearance of PC was not so remarkable as NB. The skin level of IM from the preparation containing both NB and PC was higher in the carrageenin induced edema than in the intact skin. It is suggested that the enhancement of transdermal absorption of IM and the acceleration of excretion of IM by PC may be due to the alteration of permeability by the interaction of skin membrane with PC.
The enhancing effect of lecithin (PC) on the percutaneous absorption of drugs in gelointment was investigated. Four hours after a topical application of indomethacin (IM) plus PC-gel-ointment, IM was absorbed through the intact rat back skin and moved into blood, but PC could not be found in the plasma. PC had no effect on the percutaneous absorption of IM through the stripped skin. The pretreatment with the base of gel-ointment containing only PC increased the percutaneous absorption of IM applied as gelointment 4h later. PC inhibited the peroxidation of skin lipids, but did not affect the release of SH group from skin protein. The percutaneous absorption of piroxicam (PX) and diclofenac (DF) was also enhanced by PC. It is suggested from these results that PC has a high affinity with epidermic tissue, changes the fluidity of tissue by hydration of stratum corneum, and enhances the percutaneous absorption of drugs.
The whisker growth on the surface of particles of the sodium valproate (NaVPA)-synthetic aluminum silicate (SAS) systems were investigated under various conditions of humidity and temperature. The chemical composition of whiskers was found to be the complex of NaVPA and valproic acid (VPA) with molar ratio 1 : 1. The whiskers grew in the range of the critical relative humidity (CRH) of NaVPA and a complex of NaVPA-VPA when the NaVPA-SAS systems contained 30-50% (w/w) of NaVPA. The whiskers grew at the bottom of them on the surface of particles. The whiskers grew until various length at gradually decreasing rate. The mechanism of the whisker growth was assumed that the VPA was formed from NaVPA by the surface acidity of SAS and it complexed with NaVPA. The complex moved to the roots of whiskers in a particle, then crystallized and grew as whiskers. The addition of sodium carbonate or monoethanolamine to the NaVPA-SAS systems inhibited the whisker growth. This may be due to the alkalinity of these compounds which poisoned the surface acidity of SAS. Hydrogenated castor oil also inhibited the growth of whiskers by another mechanism.
A mode of the alkaline and acidic degradation of sodium 6-[D-2-(2-(4-formyl-1-piperazinyl)-5, 8-dihydro-5-oxopyrido [2, 3-d] pyrimidine-6-carboxamido)-p-hydroxyphenylacetamido] penicillanate (1, PL-385) and structures of the degradation products were studied. Treatment of 1 with three equimolar amounts of sodium hydroxide produced a kinetically stable intermediate, (5R)-penicilloic acid (2a), which on kept at 37°C for 65h was converted into a thermodynamically stable product, (5S)-penicilloic acid (2b). Treatment of 1 with an excess of sodium hydroxide gave a deformyl derivative (3) arising from the elimination of formly group via 2. On the acidic treatment of 1, the degradation product, (5R, S)-penilloic acid (4), was yielded.
Color reaction between human serum albumin (HSA) and halogenoxanthene dyemetal complex in surfactant micellar media was investigated. As a result a highly sensitive method for the determination of HSA was proposed by use of a 3', 4', 5', 6'-tetrachlorogallein-Mo (VI) complex in a Triton X-405-polyvinyl alcohol micellar medium.