Magnesium pemoline: enhancement of learning and memory of a conditioned avoidance response.

Magnesium pemoline, a mild stimulant of the central nervous system, enhances the acquisition and retention of a conditioned avoidance response in rats. Methamphetamine and methylphenidate do not have this effect.

Thyrotropin releasing hormone: enhancement of dopa activity by a hypothalamic hormone.

Thyrotropin releasing hormone potentiates the behaviorial effects of dopa plus pargyline in mice. Because the potentiation occurs in hypophysectomized mice, as well as in normal mice, the phenomenon is independent of the release of thyroid stimulating hormone from the pituitary. Possible mechanisms and clinical implications are discussed.

Antidepressant and anticonvulsant activity of 1-(5-phenyl-4-oxazolin-2-yl)-4-substituted piperazines.

1-(5-Phenyl-4-oxo-2-oxazolin-2-yl)-4-substituted cinnamoylpiperazines and 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)-4-carbamoylpiperazine and derivatives were synthesized and evaluated for antidepressant activity in the mouse Dopa potentiation test. 1-(5-Phenyl-4-oxo-2-oxazolin-2-yl)-4-carbamoylpiperazine and derivatives were further evaluated for anticonvulsant activity in the audiogenic seizure test in mice.

Homologs of dopa, alpha-methyldopa, and dopamine as potential cardiovascular drugs.

Starting from 3,4-dimethoxyphenacyl bromide, 2-amino-4-(3,4-dihydroxyphenyl)butyric acid (homodopa) was synthesized in six steps. 5-Hydroxyhomodopa was similarly prepared. alpha-Methylhomodopa was synthesized in four steps from zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone]. alpha-Methylhomodopa showed no antihypertensive activity in the genetic hypertensive rat. Homodopa did not potentiate the behavioral effect of Dopa or inhibit Dopa decarboxylase. Homodopamine, unlike dopamine, did not increase renal blood flow in the dog.

Study of the structural requirements for dopa potentiation and oxotremorine antagonism by L-prolyl-L-leucylglycinamide.

A number of analogs of the tripeptide L-prolyly-L-leucylglycinamide (1) were synthesized and evaluated in the Dopa potentiation and oxotremorine antagonism tests. The replacement of the glycinamide residue with either the glycine methylamide, glycine, aminoacetonitrile, amino-2-propanone, semicarbazide, or beta-alaninamide residues resulted in a loss of activity in both tests. A 1:1 mixture of L-prolyl-L-leucyl-(-)-thiazolidine-2-carboxamide (8) and L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide (9) showed marked activity in the Dopa potentiation test but was unable to antagonize the tremors induced by oxotremorine. L-Prolyl-L-leucyl-L-prolinamide (11), on the other hand, was active in the oxotremorine antagonism test but inactive in the Dopa potentiation test. The replacement of the pyrrolidine ring of 1 with either a thiazolidine or cyclopentane ring system caused a loss of activity. The cyclopentanecarboxylic acid analogue 13, however, was found to have moderate activity in the serotonin potentiation test.

Drugs derived from cannabinoids. 4. Effect of alkyl substitution in sulfur and carbocyclic analogs.

Various CNS-active cannabinoids in which the alicyclic ring was thiopheno, cyclopenteno, or cyclohexeno with the alkyl substituent in various positions (structural types 1-6) were synthesized by procedures described previously. These compounds were compared in selected pharmacological tests in mice, rats, dogs, and cats. The results suggested that methyl substitution in the close proximity of the phenolic hydroxyl group strongly influenced the activity of some cannabinoids, particularly of those which had a planar five-membered alicyclic ring rather than a six-membered ring.

Drugs derived from cannabinoids. 2. Basic esters of nitrogen and carbocyclic analogs.

Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.

Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.

Ten new delta6a,10a-THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic delta6a,10a-THC analogs [8-substituted 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzo-pyrano[4,3-c]pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1-methyl-4-(4-fluorophenyl)butyl or a 1,2-dimethyl-4-(4-fluorophenyl)butyl side chain.

Drugs derived from cannabinoids. 3. Sulfur analogs, thiopyranobenzopyrans and thienobenzopyrans.

Sulfur analogs of cannabinoids corresponding to DMHP (1) were prepared utilizing the Pechmann condensation between the appropriate keto ester and (5-(1,2-dimethylheptyl)resorcinol, followed by Grignard reaction. Compounds of various structural types (2-6), which had different ring size and position of the sulfur atom substituted in the alicyclic ring, were found to be active CNS agents in pharmacological tests in mice, rats, and dogs. They showed profiles qualitatively similar to those of the nitrogen and carbocyclic analogs. Basic esters of the most interesting parent phenols 2 and 4 were also prepared and tested.

Possible correction of defective polymorphonuclear cell functions in type-2 diabetes mellitus by met-enkephalin.

In vitro pretreatment with Met-Enk of human PMNLs obtained from patients suffering from type-2 diabetes mellitus resulted in the normalization of the ROS generating system. It is assumed that Met-Enk has a modulating effect on the arachidonic acid metabolism, with a consecutive increase of the LTB4 release.

Enhancement of host resistance to viral and tumor challenge by treatment with methionine-enkephalin.

Host resistance to disease is dependent upon a number of factors. Recent evidence indicates that natural killer (NK) cells play an important role in resistance to both neoplastic and virally induced disease. Treatment of C57Bl/6 mice with methionine-enkephalin (1, 3, 10, or 30 mg/kg body weight) results in significant increases in NK activity of splenic lymphocytes 20 hours after injection of the enkephalin. Enkephalin treatment also enhances host resistance. The short-term survival of A/J female mice after HSV-2 infection was significantly increased by daily subcutaneous injections (3 mg/kg body weight) of methionine-enkephalin. Similarly, daily doses of 50 micrograms of methionine-enkephalin for 7 to 14 days inhibit the local subcutaneous tumor growth of B15 melanoma in C57Bl/6 mice.

Effect of methionine-enkephalin plus ZnCl2 on active T cell rosettes.

Methionine-enkephalin (Met-Enk) and ZnCl2 in combination enhances active T cell rosette formation of human peripheral blood lymphocytes to a greater degree than either of the agents used separately. Enhancement of rosette formation by Met-Enk plus ZnCl2 was not inhibited by the opiate receptor antagonist naloxone but was completely blocked by the zinc chelator 1,10-phenanthroline. The results suggest a relationship between zinc and Met-Enk and that zinc may be a modulator of enkephalin binding and function in the immune system as well as the nervous system.

Activation of the lipoxygenase pathway in the methionine enkephalin induced respiratory burst in human polymorphonuclear leukocytes.

In comparative studies of f-met-Leu-Phe (FMLP) and methionine enkephalin (ME) induced polymorphonuclear leukocyte (PMNL) stimulation the following results were obtained: (i) both FMLP and ME increased the intracellular killing (IK) capability of human PMNLs probably through NADPH oxidase activation, (ii) the ME-induced respiratory burst (RB) differed from the chemotactic peptide FMLP-triggered superoxide generation because the former was not accompanied by the activation of the glutathione system and the duration of the superoxide production was prolonged. The reaction was dependent on lipoxygenation, was potentiated by indomethacin (IM) and was inhibited by nordihidro-guairetic acid (NDGA), (iii) both 14C-arachidonic acid (14C-AA) release and leukotriene B4 (LTB4) synthesis of ME-treated PMNLs were elevated as compared to those of FMLP triggered cells. Our results suggest that lipoxygenation and even an increased LTB4 synthesis are involved in the ME-induced RB of leukocytes.

Neuropeptides: conductors of the immune orchestra.

There is increasing evidence for a bidirectional communications system between the immune system and the brain. Many of the substances involved in this communication appear to be neuropeptides. These findings have given biochemical validity to the clinical and epidemiological studies that have suggested that psychosocial factors can modulate the response to infections and neoplasms.

Thyrotropin releasing hormone (TRH): DOPA potentiation and biogenic amine studies.

The present study in mice demonstrated the TRH when administered over 5 days remained active in the Everett Dopamine Potentiation Test. No evidence of tolerance was observed. In fact, an accumulative effect of TRH appeared to take place. Ablation of the adrenals, ovaries, testes, pineal, spleen, parathyroid, one kidney, or thymus did disrupt this behavioral potentiation of dopamine by TRH. TRH was found to potentiate the effects of imipramine. T3, T4, and TSH were found to be active in the DOPA potentiating test. No overt toxicity was observed between TRH and pargyline or between TRH and DOPA. Toxicity was seen only when all three agents were used together. TRH was found active in young and old mice. TRH was also found active in potentiating the central effects of serotonin. Biogenic amine brain levels in mice were not altered by TRH when administered for five days. Alpha-methyl-p-tyrosine reduced the activity of TRH in the dopamine potentiation test, suggesting dopaminergic mechanisms are involved by a direct receptor interaction.

Possible association of increased rat behavioral effects and increased striatal dopamine and norepinephrine levels during the DOPA-potentiation test.

Previous reports have indicated that alpha-MSH release inhibiting hormone (MIF-1) increased the behavior occurring as a result of the dihydroxyphenylalanine (DOPA) potentiation test [3,7]. This study was undertaken to see whether dopamine (DA) or norepinephrine (NE) levels likewise increased in the test animals. The DOPA potentiation test was performed as follows: 2-4 hr before behavior measurement, 40 mg/kg of the monoamine oxidase inhibitor pargyline HCl was given orally. Two hr later this was followed by the intraperitoneal (IP) injection of MIF-1 at doses of 0.1, 0.3 or 1.0 mg/kg. Behavioral measurement was begun after the IP injection of 200 mg/kg of dl-DOPA 1-2 hr after the MIF-1. The parameters included social interaction, aggressiveness, fighting, ataxia, jumping, defecation, urination and salivation. The animals were beheaded while the behavior was still increased and the striatal area removed, placed in aluminum foil, and kept at -50 degrees C until assayed. In general, especially among the younger animals, a significant correlation (p=0.05 to p=0.01) was found between the increased behavioral responses to MIF-I and the rise in DA. Because of a few exceptions to this correlation the possibility is suggested that MIF-I might also affect behavior by acting directly on the postsynaptic membrane thus bypassing any change in NE or DA which is known to increase cycli AMP in the striatum.

Psychoneuroimmunology, new approaches to neurobehavioral testing.

A review of the literature in the field of psychoneuroimmunology was reported by Robert Ader [1]. Basically, three research approaches have been used to demonstrate a relationship between central sites within the brain that have modulatory influences on the immune system. These include: (1) both the electrical stimulation and surgical lesioning of nuclei in the hypothalamus; (2) traditional behavioral conditioning; and (3) behavioral stress studies. The mechanisms of action for the psychoneuroimmunologic response appear to be focused in three areas: (1) the autonomic nervous system, where direct anatomical connections from the brain to the immune system have been recently demonstrated; (2) the endocrine system where the individual hormones have direct and indirect effects on the immune system; and (3) enkephalins-endorphins in the brain, pituitary, and adrenals that also have direct and indirect effects on the immune system. Examples of drug effects on the above complex systems will be centered on morphine and the enkephalins-endorphins with reference to drugs of abuse, food additives, and cosmetics.