New analgesic drugs derived from phencyclidine.

Several esters of 1-(1-phenylcyclohexyl)-4-piperidinol (3), 1-(1-phenylcyclohexyl)-4-phenyl-4-piperidinol (10) and its propionate (11), and 1-(1-phenylcyclohexyl)-4-phenylpiperidine (13) were prepared and characterized. The new compounds, which are derived from phencyclidine, exerted analgesic activity in mice. The most potent is 10, which is twice as active as morphine. The antinociceptive activity of 10, 11, and 13 could be well correlated with their potency in the mouse vas deferens bioassay, and both were completely reversed by naloxone.

Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents.

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.

N-allyl analogues of phencyclidine: chemical synthesis and pharmacological properties.

Several N-allyl derivatives of 1-phenylcyclohexylamine (PCA) were prepared, and their pharmacology was briefly characterized. The mono- and diallyl derivatives had phencyclidine-like activities in mice but were less potent behaviorally than phencyclidine (PCP). None were PCP antagonists. In vitro these compounds were competitive inhibitors of butyrylcholinesterase (BChE) and protected against inhibition by DFP. In addition, these agents displaced tritiated N-methyl-4-piperidyl benzilate from mouse-brain homogenates and inhibited the effects of acetylcholine on isolated guinea pig ileum. None of these in vitro effects correlated with their PCP-like behavioral activity in vivo in mice.

Selective acetylenic 'suicide' and reversible inhibitors of monoamine oxidase types A and B.

1 A number of aromatic-N-propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5-hydroxytryptamine (5-HT), beta-phenylethylamine (PEA) and dopamine. 2 Structure activity studies with aromatic-N-propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N-methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N-propargyl portion is absolutely essential for activity and must be beta-to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property. 3 The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N-propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units. 4 The compounds AGN-1133 and AGN-1135 show most promise in Parkinson's disease or as anti-depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo. 5 A number of indoleamine derivatives were found to be reversible selective type A inhibitors.

Interaction of phencyclidine with mouse neuroblastoma cells.

Growth of mouse neuroblastoma (Nb) cell (clone M1) was not affected by phencyclidine (PCP) concentrations of 10(-6)M up to 2 x 10(-4)M, whereas 10(-3)M PCP caused a 100% inhibition of cell growth. Several PCP analogs, including the quaternary PCP methiodide, exerted effects similar to those of PCP. The uptake of [piperidyl-3,4-3H]PCP ([3H]PCP) by the Nb cells was studied using cell monolayers in Petri dishes. Non-specific entry of PCP into the cells was linear with added substrate but specific uptake exhibited saturation kinetics. The concentration for half-maximum specific uptake was 2 x 10-(5)M, and the capacity of the cells at saturation was 2-3 nmoles [3H]PCP/mg protein, at 22 degrees. The uptake rate constant was 0.2 +/- 0.05 x 10(5) (M-1 min-1) and the dissociation constant was 0.25 +/- 0.05 (min-1). Uptake was temperature dependent and was inhibited by 2,4-dinitrophenol (DNP). This may indicate that this binding represents (at least in part) an active uptake process of PCP into the cells.

Inhibition of rat liver monoamine oxidase by alpha-methyl- and N-propargyl-amine derivatives.

The inhibition of rat liver monoamine oxidase by a number of N-propargyl and alpha-methyl amine derivatives has been examined. The results indicate that alpha-methyl-substituted primary and secondary amine derivatives tend to show selectivity as reversible inhibitors towards the A-form of the enzyme. The structural features that result in selectivity in irreversible inhibitors are less easy to define and substitution of an N-propargyl group into a compound that is a selective reversible inhibitor of monoamine oxidase will not necessarily result in retention of that selectivity. Replacement of the acetylenic group in a B-selective irreversible inhibitor by an ethylenic group resulted in a compound that was a reversible inhibitor showing slight selectivity for the A-form of the enzyme.

On the opioid nature of phencyclidine and its 3-hydroxy derivative.

Phencyclidine (PCP) and its 3-hydroxy derivative (PCP-3-OH) caused a dose-dependent, naloxone reversible inhibition of the response of the guinea pig ileum to electrical stimulation. Unlike PCP, PCP-3-OH exerted an opioid antagonistic effect in the mouse vas deferens bioassay. Whereas both compounds displayed a high affinity in displacing [3H]SKF-10047 binding to rat brain membranes, PCP-3-OH displayed a high affinity to [3H]morphine receptors also. The mediation of alpha- and mu-receptors in the opioid effects of these drugs is discussed.

Receptor binding and antinociceptive properties of phencyclidine opiate-like derivatives.

The relative potencies of a new series of phencyclidine (PCP) analogs for the displacement of [3H] morphine binding from rat brain homogenates are well correlated with the relative antinociceptive potencies in the test of writhing induced by acetic acid (0.6%). One group of compounds exerts a completely naloxone-reversible analgesic effect, while the effects of a second group are partially reversed by naxolone. These findings and the structural differences between the two groups suggest that their analgesic is mediated through different opiate receptors.

A national monitoring system for congenital malformations in Israel.

In 1976 the Department of Maternal and Child Health in Israel established, at minimum cost, a national system for reporting of congenital malformations. The system is based on hospital reporting of all live births through a special form attached to the live birth certificate. Compliance of reporting has reached 80 to 90%. Data obtained are tabulated and circulated monthly. It was found that forms that were received later reported a relatively higher percentage of congenital anomalies.

Enzymatic activity in crude oil contaminated rats.

The activity of enzymes found in the plasma, malate dehydrogenase (MDH) and lactate dehydrogenase (LDH), and enzymes from erythrocytes, glucose-6-phosphate dehydrogenase (G-6-PDH) and catalase, was studied in rats contaminated by crude oil. Crude oil (tube fed) contamination caused a significant increase in MDH and LDH activity 96 hr after contamination while a decrease in activity was noted in 6-6-PDH and catalase. An additional contamination (1 week after the first contamination), measured 96 hr after contamination, caused a relative decrease in MDH and LDH activity while there was a contrasting relative increase in G-6-PDH and catalase activity. After a recovery period of 3 weeks the only significant change was an increase in catalase activity.

Malic dehydrogenase from tamarix roots: effects of sodium chloride in vivo and in vitro.

Soluble and mitochondrial malic dehydrogenases (MDH) were isolated from root tips of the halophyte Tamarix tetragyna L. grown in the presence and absence of NaCl. The activity of the enzymes isolated from root tips grown in the presence of NaCl was lower than that of the enzymes isolated from roots grown in absence of NaCl. The mitochondrial MDH was much more sensitive to salinity than the soluble MDH. The soluble enzyme from roots grown in NaCl had a higher Km for malate and lower Km for NAD than enzyme from the control roots. Addition of NaCl in vitro at 72 mM significantly stimulated the reductive activity of soluble MDH, while higher NaCl concentrations (240 mM and above) depressed enzyme activity. The inhibition of enzyme activity by various salts was found to be in the order MgCl(2) > NaCl = KCl > Na(2)SO(4). Mannitol at equiosmotic concentrations had no effect. Substrate inhibition, typical for oxaloacetate oxidation, was not observed at high NaCl concentrations in vitro and high substrate concentrations neutralized the inhibitory effect of NaCl. Increased coenzyme concentrations had no effect. In vitro NaCl increased the Km for malate and oxaloacetate already at relatively low concentrations. At the same time NaCl decreased the Km for NAD and NADH. The inhibitory effect of NaCl on enzyme activity seems not to be due to the effect on the Km alone. Soluble and mitochondrial MDH had different responses to pH changes, mitochondrial MDH being more sensitive. Mitochondrial MDH released from the particles had a similar response to that of the entire particles. Changes of pH modified the effect of NaCl on enzyme activity. It was postulated that NaCl apparently induces conformational changes in the enzyme.

Effect of Salinity on Respiratory Pathways in Root Tips of Tamarix tetragyna.

Oxygen uptake in the presence of exogenous glucose was lower in Tamarix root tips grown in saline media than in those grown in Hoagland solution. This effect was not overcome by raising the external glucose concentration.Glucose uptake and CO(2) evolution were depressed in the presence of NaCl. This effect was observed also when roots were exposed to salinity only during growth but not during uptake. Increasing the external concentration of glucose from 0.01 to 1 mm induced only a 10-fold increase in glucose uptake and CO(2) evolution. However, (14)C evolved in CO(2) as percent of (14)C absorbed, remained constant at all salinity treatments, and was similar at both glucose concentrations.Salinity above 120 mm NaCl increased the percentage of absorbed glucose oxidized via the pentose phosphate pathway, but did not affect the glycolytic pathway. At the same time, salinity depressed the glucose-6-P dehydrogenase, pyruvate kinase, and oxidative phosphorylation. These effects become most evident at a salinity level of about - 10 atm (240 mm), a concentration which is rarely exceeded in the root zone of the natural habitat of the plants.We concluded that Tamarix is reasonably well adapted to the conditions of its habitat, and that salinity affects its root metabolism differently than it does that of pea roots.

The effect of phencyclidine on noradrenaline uptake by bovine chromaffin granules.

The effects of the psychotomimetic drug, phencyclidine, on the reserpine sensitive uptake of (-)noradrenaline, on the reserpine resistant uptake of tryptamine, and on catecholamine release were studied in vitro using bovine chromaffin granules. Phencyclidine inhibited the uptake of (-)noradrenaline and tryptamine in a concentration-dependent manner. It caused 50% inhibition of (-)noradrenaline uptake at 2 X 10(-4)M and of tryptamine uptake at 7 X 10(-4)M. Release of catecholamines was not affected by phencyclidine at 0 degree C and pH 6--8 in concentrations up to 8 X 10(-3)M, whereas at 37 degrees C the drug (4 X 10(-3)M) caused a release that was increased when the pH was raised from 6 to 8. Since the effects of phencyclidine on chromaffin granule uptake and release are observed at high concentrations of the drug only, there is no evidence that these effects are relevant to the in vivo effects of the drug.