Ivan Krejčí

Vasopressin analogs: Sedative properties and passive avoidance behavior in rats

The effects of several types of vasopressin analogs that are considered to be resistant to some of the physiologically significant enzymatic systems were investigated utilizing rats trained in a passive avoidance task. Enhancement of avoidance latencies was observed 2, 7 and 13 days after the single learning trial when deamino-carbavasopressins, triglycyl-8-lysine-vasopressin or its des-glycinamide derivative, and deamino-D-arginine-vasopressin were given shortly after the learning trial in the dose of 1 microgram s.c. (8-L-Arginine)deamino-6-carba-vasopressin and (8-L-ornithine)deamino-6-carba-vasopressin were also active in the dose of 0.1 microgram. Lysine vasopressin and its des-glycinamide derivative failed to enhance avoidance latencies in part of the experiments if doses of 0.3--3 micrograms were administered and 7 or 13 day intervals were used between the learning and the test trials. Enhancement of avoidance latencies was also observed, if some of the peptides were injected 20 min but not 120 or 180 min before the test trial. Marked depression of exploratory behavior of rats in an open field was found after s.c. injections of low doses (1--3 micrograms kg-1) of deamino-carba-vasopressins. Higher doses (10--30 micrograms kg-1) induced sleep-like immobility not accompanied by ataxia or catalepsy.

Pharmacology of cyclic analogues of deamino-oxytocin not containing a disulphide bond (carba analogues)

Abstract A study was made of the uterotonic, antidiuretic and pressor activities and the effect on the isolated mammary gland of 6 deamino-oxytocin analogues not containing a disulphide bond: [1,6-α-deaminocystathionine] -oxytocin (deamino-carba 1 -oxytocin, Car-1 -OT), [6,1-β-deaminocystathionine] -oxytocin (deamino-carba 6 -oxytocin; Car-6-OT), [1,6-α-aminosuberic acid] -oxytocin (deamino-dicarba-oxytocin; Asub-OT), [1,6-deaminolanthionine] -oxytocin (Lan-OT), [1,6-α-aminopimelic acid] -oxytocin (Apim-OT), and [1,6-deaminohomolanthionine] -oxytocin (Hlan-OT). The values of biological activity obtained in the individual tests show that the presence of the disulphide bridge in the hormone molecule is not a prerequisite for the interaction of oxytocin with the receptors. The carba analogues of deamino-oxytocin with a modified ring size have all in all decreased activity with the exception of the effect of Hlan-OT on the mammary gland where this analogue has the highest activity of all the compounds tested.

Prolonged action of deamino-carba analogues of oxytocin on the rat uterus in vivo

Abstract Deamino-oxytocin and some of its ‘carba’ analogues have a protracted effect on the rat uterus in vivo. Comparison of the elimination constants of the individual analogues of oxytocin and of deamino-oxytocin shows that the lower elimination rate of the analogues depends on the absence of the amino group in position 1 of the peptide chain. The individual modifications of the disulphide bridge influence the value of the elimination constants in different ways. Only the modification of hemicystine in position 6 of deamino-oxytocin resulted in an analogue with an even more prolonged action. The analogues with the most protracted action on the uterus, i.e. deamino-dicarba-oxytocin and deamino-6-carba-oxytocin, had a shorter antidiuretic action than oxytocin.

Effect of magnesium on the action of oxytocin and a group of analogues on the uterus in vitro

Abstract The inclusion of 0.5 mM Mg in the bathing medium increase the sensitivity of the rat uterus to the stimulant action of oxytocin and to analogues modified in sequence position 3. The log dose-response curves undergo a parallel displacement towards lower dose levels; either the amplitude of the first contraction or the summed amplitudes of the contractions over a standard period is used as the measure of the response. A similar potentiation by magnesium is observed in media of increased potassium concentration. The potency relative to pituitary extract of eight of the analogues is increased in the presence of magnesium. Within the series of peptides, the degree of potentiation is inversely related to the potency. The site of magnesium potentiation is thought to be at or close to the site of hormone action.

Passive avoidance behavior: Opposite effects of oxytocin analogs with agonist and antagonist properties

Deamino-6-carba-oxytoxin (dC60), a potent oxytocin analog considered to be resistant to some of the physiologically significant enzymic systems, and N-alpha-acetyl-[2-O-methyltyrosine]oxytocin (AMTO), an analog acting as a competitive inhibitor of oxytocin on the rat uterus, were studied in rats trained in a passive avoidance task. Subcutaneous administration of dC60 (5-50 microgram . kg-1) during different phases of the passive avoidance learning paradigm attenuated avoidance latencies; the results indicated that the drug induced state-dependent learning. AMTO (5-20 microgram . kg-1) enhanced avoidance latencies when administered subcutaneously before training trials and/or before retention test trials. This effect occurred in both males and females. The analogs did not influence exploratory behavior in open field. The results suggest that oxytoxin, in contrast to vasopressin, may impair memory processes. However, both analogs failed to influence the passive avoidance response when administered after training. This finding indicates that dC60 and AMTO did not influence the mechanism of memory consolidation whereas vasopressin and oxytoxin had a marked effect.

Action of [1,6-di-alanìne]-oxytocin and [1,6-di-serine]-oxytocin on the rat uterus and mammary gland in vitro.

Abstract [1,6-Di-alanine]-oxytocin (dethio-oxytocin) and [1,6-di-serine]-oxytocin have an oxytocin-like contractile effect on the rat mammary gland strip and, in some experiments, on the isolated rat uterus. The potencies are in the range of mU per mg. The contractile response is blocked by the specific oxytocin antagonist, carbamyl-methyloxytocin. On the isolated uterus the analogues can also act as inhibitors of the contractile response to oxytocin. A low calcium concentration in the organ bath, the absence of magnesium, and a low temperature favour the inhibitory properties. The antagonism is surmountable, reversible and probably competitive.

Synthesis and Analgesic Activity of Some Quinazoline Analogs of Anpirtoline

New condensed derivatives of anpirtoline, in which the pyridine ring is replaced with quinoline, quinazoline, 7‐chloroquinoline, and 7‐chloroquinazoline nuclei, have been synthesized. Their receptor binding profiles (5‐HT1A, 5‐HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. The analgesic activity of compounds 4e—4g, and 4l are at least comparable to that of clinically used drugs flupirtine and tramadol under the same conditions.

Synthesis and analgesic activity of some condensed analogs of anpirtoline.

New condensed derivatives of anpirtoline, in which the pyridine ring is replaced with quinoline, isoquinoline, quinazoline, and phthalazine nuclei, have been synthesized. Their receptor binding profiles (5‐HT1A, 5‐HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. The analgesic activity of compounds 7d, 8b, 8c, and 8e are at least comparable to that of the clinically used drugs flupirtine and tramadol under the same conditions.

Actions of neurohypophysial hormone analogues on perfused isolated rat caudal artery

Abstract Rat caudal artery segments were perfused at a constant rate with Krebs solution and the perfusion pressure was recorded. The ratio of vasoconstrictor activity on this preparation to rat pressor activity for oxytocin and seven neurohypophysial hormone analogues differed from the corresponding ratio for standard posterior pituitary extract and for the vasopressins, in most cases significantly ( p The O-methyl- and O-ethyltyrosine analogues of oxytocin and lysine vasopressin and also [2-p-ethylphenylalanine]-oxytocin had little or no constrictor effect on the isolated artery and inhibited its response to the hormones. The pA 2 values for this inhibition were of the same order (5.4–5.9) for all five antagonists. The effects of epinephrine and norepinephrine on the responses of the isolated artery to lysine vasopressin and oxytocin were variable but in no case was a vasodilator response to either peptide observed.

Synthesis, analgesic activity, and binding properties of some epibatidine analogs with a tropine skeleton

A series of epibatidine analogs and their positional isomers bearing an 8‐azabicyclo[3.2.1]octane moiety is described. Also some of their simplified analogs bearing a 3‐piperidine moiety are reported. Their receptor binding profiles (5‐HT1A, 5‐HT1B, M1, M2, neuronal nicotinic receptor) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Some of the compounds, especially those containing an 8‐azabicyclo[3.2.1]oct‐2‐ene moiety possess high afinity for the nicotinic cholinergic receptor. The most analgesically active compounds are also highly toxic. Optimized structures (PM3‐MOPAC, Alchemy 2000, Tripos Inc.) of compounds 1—9 were compared with that of epibatidine.