Effects of amphazide (a hydrazide of phosphorylated carboxylic acids) and tetramezine (a diaziridine derivative) on central dopaminergic structures

Abstract

Amphazide and tetramezine, two recently synthesized compounds with antidepressant and nootropic activities; were found to have dopamine-positive activity in animals injected with apomorphine, L-Dopa, or haloperidol. Amphazide expressed this activity in most tests only when given in multiple doses, whereas tetramezine expressed it well even after a single dose.Key Words: amphazide; tetramezine; dopamine-positive activity Dopaminergic (DA) structures are involved in memory processes, promoting the recall of what was learned long ago [13,15] and, when activated, contributing to effective restoration of forgotten habits [15]. There is evidence that the DA system is implicated in mediating the effects of certain antidepressants [1,3].The purpose of this study was to investigate how central DA structures might be influenced by two recently synthesized compounds with antidepressant and nootropic activities --amphazide, which is a hydrazide of phosphorylated carboxylic acids, and tetramezine, which is a diaziridine derivative. MATERIALS AND METHODSThe study was conducted on 170 random-bred mice (body weight 17-22 g) and 50 random-bred rats (body weight 150-200 g).Amphazide and tetramezine (TM) were injected intraperitoneally at 90 mg/kg body weight either once or ten times once daily, and their effects on apomorphine-induced hypothermia and stereotypy, LDopa-induced hypothermia and alterations in exploratory and motor activities, and haloperidol-induced catalepsy were evaluated. State Medical University, KazanHypothermia was produced in mice by a subcutaneous injection of apomorphine at 25 mg/kg, and their body temperature was recorded with an electric thermometer 1 and 2 h postinjection.The total duration of sterotypy and the intensities of its components (licking, sniffing, and gnawing) were measured in rats 1 h after a subcutaneous injection of apomorphine at 20 mg/kg. Skin temperature and exploratory and motor activities (the number of holes explored and of lines crossed in an open field) were recorded in mice 1 h after a subcutaneous injection of L-Dopa at 150 mg/kg.The severity of catalepsy was evaluated by the ability of mice to retain an awkward posture (with the hind legs on a support 30 mm high and the forelegs on the table) for 60 sec at 10, 60, and 120 min after haloperidol injection at 5 mg/kg.The results were statistically analyzed by Student's t test. RESULTSAmphazide potentiated the effects of apomorphine only in multiple doses, enhancing the hypothermia in mice (Fig. 1) and prolonging the stereotypy in rats (Table 1); the recording of individual stereotypy components in rats showed longer sniffing times in comparison with the control group. In contrast, TM

Stereodynamics of tetramezine

“…Tetramezine [1,2‐bis(3,3‐dimethyldiaziridin‐1‐yl)ethane] shows antidepressant and dopamine‐positive activity1, 2 inhibiting the enzyme monoamineoxidase 3. Its bioavailability4 to dogs from intestine‐insoluble tablets, its pharmacokinetics5 and metabolization pathways6 in rats, and its excretion7 from rats have all recently been investigated by Prokopov et al Information about the stereochemical integrity of chiral drugs is of great importance, because, in the worst case, one of the stereoisomers can exhibit toxic effects8 and facile racemization makes stereoselective synthesis or separation obsolete 9–11.…”

Nitrodiaziridines: Unattainable yet, but Desired Energetic Materials

“…Three-membered heterocycles have a high potential in organic synthesis since the high strain energy and facile cleavage of the polarized carbon-heteroatom bond ensure their efficient use as synthetic equivalents of 1,3-zwitter-ionic synthon. − Diaziridines, saturated three-membered heterocycles with two nitrogen atoms (cyclic hydrazines), possess a unique set of properties. First of all, the diaziridine ring is prone to ring expansion reactions, resulting in various five-to-eight-membered mono- and biheterocyclic structures. − Second, diaziridine derivatives reveal various types of neurotropic activity and may serve as pharmacologically active agents acting on the central nervous system. − In addition, diaziridines contain configurationally stable nitrogen atoms (the inversion barriers are 18–27 kcal mol –1 ) and are fairly rare objects for studying the stereochemistry of the nitrogen atom. − Importantly, diaziridines combine high positive enthalpy of formation due to the strained nature of the three-membered ring and the presence of the hydrazine moiety along with their low toxicity. These advantages make diaziridines applicable as potential fuels for liquid rocket propellants instead of toxic hydrazine derivatives , as well as precursors for the synthesis of other high-energy structures.…”

Stereodynamics of Small 1,2‐Dialkyldiaziridines

“…Many of the pioneering contributions to this field of research were made by Schmitz et al in the following decades. [4][5][6] Diaziridines show pronounced neurotropic activity, [7][8][9][10][11][12][13][14] and can be used in the synthesis of various heterocyclic compounds. 15 In these compounds, two chirotopic nitrogen atoms are present.…”