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The opiate-like effects of eseroline, a physostigmine derivative, were studied in different tests. The antinociceptive effect of eseroline given s.c. and intracerebrally could be detected in the rat hot plate test and was reversed by naloxone. The apparent pA2 values of naloxone demonstrated with eseroline and morphine were found to be equal, suggesting an effect on similar receptors. Eseroline also had opiate agonist activity on the isolated longitudinal muscle strip of guinea pig ileum and isolated nictating membrane of the cat: presynaptically, it inhibited the contractions evoked by stimulation and its effect was antagonized by naloxone. Eseroline reduced acetylcholine release from the myenteric plexus of the longitudinal muscle strip when the cholinesterases had been inhibited by physostigmine. In addition, it was also found that eseroline antagonized the inhibitory effect of normorphine in the longitudinal muscle strip and potentiated the effect of exogenous acetylcholine on smooth muscle, both effects being attributed to its anticholinesterase activity. The analgesic effect of eseroline was not related to its anticholinesterase activity.

1. Wird das isolierte Froschherz mit Ringer-Losung ausgewaschen, die das 16–54fache der normalen KCl-Menge enthalt, bleibt es in Diastole stehen. Sofern man mit dem Waschen aufhort und die das Stehenbleiben in der Diastole verursachende KCl-Losung in der Kanule belast, kann sich das Herz dieser ungunstig zusammengesetzten Losung anpassen, und trotz des grosen K-Uberschusses kann die Kammertatigkeit spontan wieder zustande kommen. 2. Die Adaptationsfahigkeit bleibt nach Anlegen der I.-Stannius-Ligatur erhalten; sie fehlt jedoch nach Anlegung der II.-Stannius-Ligatur. 3. Nach der Adaptation an den K-Uberschus zeigt der K-Gehalt der in der Kanule befindlichen Flussigkeit keine wesentliche Veranderung. 4. Das isolierte Froschherz kann sich an Ca bzw. K und Ca-Mangel adaptieren. Diese Adaptation ist an die Anwesenheit des Vorhofs gebunden. 5. Die Adaptation an Ionen-Mangel ist mit einer Abgabe der fehlenden Ionen nicht erklarbar.

It had been shown previously that in rat vas deferens prostaglandins fail to influence neurochemical transmission. Therefore, this preparation provides a possibility for studying the transmitter release in a preparation in which any interaction with prostaglandins was in all likelihood excluded.

The effect of noradrenaline released either by sympathetic nerve stimulation or guanethidine added to the organ bath has been studied on acetylcholine release from parasympathetic nerve terminals and compared with the effect of exogenous noradrenaline. Sympathetic nerve stimulation, guanethidine and noradrenaline reduced the release of acetylcholine from resting rabbit intestine by up to 70%. Sympathetic stimulation and guanethidine failed to reduce acetylcholine release in preparations previously depleted of noradrenaline. Noradrenaline added to the bath still remained effective. The fact that noradrenaline released is capable of inhibiting acetylcholine release supports the concept that noradrenaline physiologically controls the release of acetylcholine.

Monoamine oxidase (MAO) inhibitors are potentially important drugs, especially in the treatment of psychiatric disorders. However, non-specific MAO inhibitors block the action of the MAO which are involved in detoxifying various amines derived from various foods, especially cheese, allowing these amines to exert a hypertensive reaction (the so-called ‘cheese effect’). This has limited the use of MAO inhibitors as therapeutic agents. However, the discovery of two types of MAO, and the development of (-)deprenyl, the first highly potent, irreversible MAO inhibitor without the ‘cheese effect’ may change this situation.

In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.

In rats, a selective inhibition for 3 weeks of monoamineoxydase (MAO) type B elicited by daily doses of pargyline (2.5 mumol/kg) or (-)-deprenyl (1 mumol/kg) attenuated the NE dependent stimulation of cortical adenylate cyclase and reduced the number of brain recognition sites for beta-adrenergic receptor ligands. Similar actions were not elicited by a comparable dose regimen of (+)-amphetamine. Hence the inhibition of MAO B mimicks responses that are typically elicited by antidepressants. The molecular nature of the mechanisms involved cannot be understood, however, these mechanisms may not be identical for pargyline and (-)-deprenyl because this drug but not pargyline increased the number of [3H]imipramine recognition sites. Even high daily doses of pargyline (100 mumol/kg, for 3 weeks) failed to change [3H]imipramine binding though they still down regulated beta-adrenergic recognition sites, the NE stimulation of adenylate cyclase and the Bmax of [3H]mianserin and [3H]spiroperidol binding.

Parkinson’s disease (PD), first described in 1817 as paralysis agitans by James Parkinson in his “Essay on the Shaking Pulsy,” is characterized by tremor, bradykinesia, rigidity, and a postural defect. The usual distinction between postencephalitic and idiopathic PD is of little practical importance as about 85–90% of the patients suffer from the idiopathic form of the illness.

(-)Deprenyl, a selective inhibitor of MAO-B, was found to be 60 times less potent in inhibiting intestinal MAO in the rat than clorgyline, the selective inhibitor of MAO-A. This is one of the reasons why (-)deprenyl is safe with respect to the hazards involved in combination with a variety of foods and drugs and its administration is not contraindicated in parkinsonian patients.

The influence of longterm deprenyl treatment on the sexual performance and lifespan of male rats was studied. One hundred and thirty two rats were treated from the end of their 2nd year of life either with saline (1 ml/kg, s.c.) (n = 66) or with deprenyl (0.25 mg/kg, s.c.) (n = 66) three times a week until death. Whereas none of the two-year-old saline-treated rats displayed full scale sexual activity, this appeared in 64 out of 66 rats on deprenyl. The longest living rat in the saline-treated group lived 164 weeks. The lifespan of the group was 147.05 +/- 0.56 weeks. The shortest living animal in the (-)deprenyl-treated group lived 171 weeks and the longest living rat died during the 226th week of its life. The lifespan was 191.91 +/- 2.31 weeks. This is the first instance that a well aimed medication prolonged lifespan of members of a species beyond their maximum age of death (182 weeks in the rat). A close relation between sexual activity and lifespan was detected.

Long-term experiments on male rats revealed that better performers in the mating test are better learners in the shuttle box and the more active animals live significantly longer than their less active peers. It was established by the aid of (-)deprenyl, a highly specific chemical tool, which increases superoxide dismutase activity in the striatum, facilitates the activity of the nigrostriatal dopaminergic neurons with utmost selectivity, and protects these neurons from their age-related decay, that the efficiency of a male rat in behavioral tests, as well as the duration of its life are striatal dopamine dependent functions. As a measure of striatal function, sexual activity was tested once a week in a group of male rats (n = 132) from the 24th month of their life. Because of the age-related decay of this function none of the 2-year-old animals displayed full scale sexual activity. By dividing the group equally the rats were treated with saline (1 ml/kg, s.c.) and deprenyl (0.25 mg/kg, s.c.), respectively, three times a week. In the saline-treated group (n = 66) the last signs of sexual activity vanished to the 33rd week of treatment. (-)Deprenyl treatment restored full scale sexual activity in 64 out of 66 rats. The longest living rat in the saline-treated group lived 164 weeks. The average lifespan of the group was 147.05 +/- 0.56 weeks. The shortest living animal in the (-)deprenyl-treated group lived 171 weeks and the longest living rat died during the 226th week of its life. The average lifespan was 197.98 +/- 2.36 weeks, i.e. higher than the estimated maximum age of death in the rat (182 weeks). This is the first instance that by the aid of a well-aimed medication members of a species lived beyond the known lifespan maximum.

Overweight is a serious predisposing factor to ill-health and mortality, and fat phobia exists due to the present dominance of the lean body image in the richer part of the world. These two recognitions have considerably increased interest in pharmacologic and other strategies for the treatment of obesity. Despite all efforts, however, none of the numerous anorectics marketed during the last two decades have lived up to expectations in 2-3-year follow­ up studies. There is still a desperate need to provide a solution to the problem of obesity. It was unexpectedly observed that a number of endogenous substances, mainly peptides, with a well-known physiological spectrum, like glucagon, insulin, cholecystokinin, calcitonin, etc., also inhibit food intake, and that the satietins, a hitherto unknown family of a,-glycoproteins in human and mammalian sera have potent and selective anorectic activity. These observations represent the most promising new line of research. This line intends to understand better the control of food intake, to clarify the etiology of feeding-related pathologies, and to elaborate a more efficient therapy for obesity

Isolated central ear arteries of rabbits were perfused with Krebs solution at a constant flow rate of 2–7 ml/min. Pressure changes to periarterial nerve stimulation (1, 3, 10 and 30 Hz; 5–32 pulses) and to noradrenaline were measured in the presence and absence of prostaglandin E 1 (PGE 1 ). This substance in concentrations of 7 × 10 −9 – 4.5 × 10 −7 produced a dose-dependent inhibition of constrictor responses to nerve stimulation. The degree of inhibitory action of PGE 1 became progressively less as the frequency or length of stimulation was increased. Prostaglandin E 1 (1.1 × 10 −7 M) failed to affect the constrictor responses to noradrenaline and it markedly reduced the stimulation-evoked release of radioactivity from arteries incubated with [ 3 ]noradrenaline. The results indicate that PGE 1 inhibits the vasoconstrictor responses of rabbit ear artery to nerve stimulation by reducing the release of the adrenergic transmitter.

The N -demethylation by rat liver of azidomorphine and azidocodeine, new morphine derivatives with low tolerance and dependence capacity in animals and men, was compared to that of morphine. The drugs were administered intraperitoneally, in progressively increasing doses during a period of 27 days, until daily injections of 150 mg/kg of morphine HCl, 3 mg/kg of azidomorphine tartrate and 8 mg/kg of azidocodeine tartrate as maintenance doses were reached. The analgesic ratios of morphine:azidomorphine:azidocodeine were found to be 1:293:13 in the hot plate test. The liver of rats treated for 4 weeks with morphine completely failed to N -demethylate the narcotic drugs. The enzymic N -demethylation of morphine in animals exposed to more prolonged treatment (7–10 weeks) was about 30–40 per cent that of the saline treated controls. Withdrawal of morphine led to a complete restoration of the enzyme activity. In the azidomorphine- and azidocodeine-treated groups however, the N -demethylation capacity of the liver after 4 weeks treatment was only moderately reduced and in rats treated for 7 and 10 weeks, respectively, no decrease in the enzyme activity was observed. The profound difference between azidomorphine, the most potent known analgesic among the semisynthetic morphine derivatives, and morphine demethylation, parallels the difference in their tolerance capacity in animals and man.

The kinetic parameters of azidomor phine (6-deoxy-6-dihydro-azido-isomorphine), a new highly potent semisynthetic derivative of morphine was studied on the longitudinal muscle strip of guinea-pig ileum and with the hot-plate method. Azidomorphine reduced the neuro-effector transmission in the longitudinal muscle strip and this effect was antagonized by naloxone in a competitive manner. In contrast to morphine, the agonist concentration (ID50) of azidomorphine failed to exert an antagonistic effect in this test. The analgetic effect of azidomorphine was much more easily antagonized by naloxone than that of morphine. However, the opposite was observed in the hot-plate test with azidomorphine and morphine when nalorphine was used as antagonist. The significant differences in the kinetics between morphine and azidomorphine indicate that some important differences in their interaction with the receptor might exist between the two structurally related substances.

Gastrin- and cholecystokinin-like polypeptides have been found to release acetylcholine from the Auerbach plexus of longitudinal muscle strips of guinea pig ileum. The evidence is consistent with the view that contractions of intestine in response to these peptides are due to the acetylcholine released. Tetrodotoxin inhibited actions of peptides both on acetylcholine release and on mechanical responses of intestine; however, hexamethonium failed to affect their actions, indicating that their site of action is situated on non-nicotinic receptors of ganglionic cells. C-terminal octapeptide amide of cholecystokinin-pancreozymin and caerulein produced significant acetylcholine release in concentrations as low as 9 × 10 −10 and 7.5 × 10 −10 M, respectively. Human gastrin I was much less effective, its threshold concentration being 7 × 10 −8 M. Both exogenous and endogenous noradrenaline reduced both the acetylcholine release and the contractions of longitudinal muscle produced by peptides. Noradrenaline acted at a presynaptic site and its action was mediated through α receptors. It is concluded that gastrointestinal hormones may play a role as hormonal factors in regulating gastrointestinal motility, and their effect is continuously controlled by the tonic activity of the sympathetic nervous system which reduces acetycholine release.

Our aim was to study the fate of (-)-1-(benzofuran-2-yl)-2-propylaminopentane .HCl [(-)-BPAP] in rats, using radio-labelled compound [(-)-BPAP-14C]. Radioactivity was measured by liquid scintillation technique and the tissue concentrations of radioactivity were calculated on the basis of the specific activity of (-)-BPAP-14C and the values are given in ngeq./g. Radioactivity was well absorbed after i.p., s.c. and oral treatment and Cmax has been reached at 30 to 60 min following drug administration. A second peak, detected at 4 hours, indicated enterohepatic circulation of the substance. The highest tissue levels of radioactivity were reached at 30 min following s.c. treatment. The time-related changes of radioactivity were measured in nine selected brain regions after s.c. administration of (-)-BPAP-14C. A similar distribution profile was observed in the brain regions with a peak level at 30 min. Radioactivity is preferentially eliminated through the urine, the secondary route of excretion was the stool. More than 90% of the substance was recovered in the excreta during 72 hours. The t1/2 beta was found to be 5.5 to 5.8 hours. (-)-BPAP was well absorbed and penetrated the brain. Its elimination was fast and enterohepatic circulation was observed in rats.

A structure-activity relationship study has revealed the importance of the aromatic ring and the optimum length of the chain between the aromatic ring and the nitrogen for the selective inhibition of MAO-B. Among the (−)deprenyl derived new compounds described in this study N -methyl- N -propargyl-(2-furyl-1-methyl)-ethylammonium. HCl(U-1424) seems to be the most promising selective inhibitor of MAO-B.