Karel Jošt

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.

Oxytocin analogs effective as noncompetitive inhibitors in uterotonic test.

Deamino-1-carba-oxytocin analogs with a chemically reactive group in position 4 were demonstrated to act as noncompetitive oxytocin inhibitors in the assay on isolated rat uterus.