A. P. Skoldinov

New endogenous dipeptide cycloprolyl-glycine is similar to piracetam by its mnemotropic selectivity

The effects of endogenous dipeptide cycloprolyl-glycine on learning and memory in the model of postconvulsive retrograde amnesia of passive avoidance response in rats depended on the administration schedule. The dipeptide prevented retrograde amnesia, when injected prior to learning, had no effect after postlearning administration, and aggravated amnesia, when injected immediately before retrieval. These data suggest that cycloprolyl-glycine is similar to the standard nootropic piracetam by its mnemotropic activity.

Synthesis and nootropic activity of pyrrolidino[1,2-a]diazacycloalkanes

Previously we have reported on the synthesis and characterization of compounds representing two groups of piracetam analogs, based on pyroglutamic acid [ 1 3 ] and proline [4, 5]. Among the proline-containing compounds possessing nootropic properties, the maximum activity was observed for the ethy i ester of N-pheny lacety lproly Iglycine [6]. In this paper we present data on the synthesis of a new group of the pyracetam analogs, pyrrolidino[1,2-a]diazacycloalkanes, based on the natural pyrrolidine-containing amino acids. We have also studied the antiamnesic activity of the synthesized compounds. We believe that investigation of these compounds, belonging to the class of conformationallyrigid structures, may elucidate the steric requirements of receptors with respect to the nootropic ligand conformation. We have synthesized the following bicyclic derivatives of proline with six, seven, and eight-membered cycles: pyrrolidino[l,2-a]-2,5-diazacyclohexane-l,4-dione (I), pyrrolidino[l,2-a]-2,6-diazacycloheptane-l,5-dione (II), pyrrolidino[1,2-a]-2,7-diazacyclooctane-l,6-dione (III), and 3-carboethoxyethylpyrrolidino[ 1,2-a]-2,5 -diazacyclohexane1,4dione (IV). The bicyclic derivatives of pyroglutamic acid differed by the positions of carbonyl groups in the six-membered cycle, as in pyrrolidino[l,2-a]-2,5-diazacyclohexane1,3,6-trione (V) and pyrrolidino[l,2-a]-2,5-diazacyclohexane-l,4,6-trione (VI), and by the presence of the substituent in the six-membered cycle, as in 2-acetylpyrrolidino[1,2-a]2,5-diazacyclohexane1,4,6-trione (VII).

Acyl derivatives of phenothiazine and their dibenzazepine analogs: Structure and antiarrhythmic activity

The systematic work of chemists and pharmacologists of the Institute of Pharmacology, Academy of Medical Sciences of the USSR in the series of dialkylaminoacyl derivatives of phenothiazine ended with the discovery of original highly effective antiarrhythmic agents, ethmosine, and ethacizine [2, 3, 5-8], which have been evaluated highly by clinicians in the USSR and abroad [9-11, 15, 16]. The correlations between chemical structure and antiarrhythmic activity revealed for the example of these phenothiazine derivatives have permitted the discovery of compounds with promising antiarrhythmic properties among the corresponding analogously constructed aminoacyl derivatives of dibenzazepine, representing a tricyclic nitrogencontaining system related to phenothiazine. Bonnecor, which possesses an original spectrum of antiarrhythmic action [12-14, 17], was discovered in this way and was the fruit of the joint efforts of coworkers of the Institute of Pharmacology of the Academy of Medical Sciences of the USSR and the Germed enterprise from the German Democratic Republic.

Nootropic action of proline-based topological analogs of piracetam

Increasing attention has recently been given to nootropic compounds that specifically activate higher cerebral integrative functions which facilitate learning and memory processes [2, 8, 12]. Piracetam is a principal nootropic preparation. Through peptide synthesis we obtained a new group of nootropic compounds that are dipeptide analogs of piracetam with N-terminal pyroglutamic acid. We have presented neuropharmacological data that indicate their action via special nootropic receptors [3, 5, 7]. Later we expanded this group of nootropes based on natural a-amino acids by utilizing N-acyl derivatives of another pyrrolidine-conraining amino acid, i.e., L-proline [6]. The amide of N-acetyl-L-proline (I) exhibited the greatest nootropic effect,

Antagonism between pyracetam and proline in their effect on memory

: Cytochemistry was used to measure the activity of succinate dehydrogenase (SOD), lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6-PDH) in rat peritoneal macrophages under the action of the endogenous immunostimulant tuftcin (tre-lys-pro-arg) during phagocytosis of latex particles and at rest. Tuftcin did not affect the activity of the study enzymes in non-phagocytic cells. Elevation of the peptide concentration to 0.25 micrograms/ml and higher in phagocytic macrophages activated G-6-PDH and lowered the activity of LDH. Tuftcin did not alter the activity of SOD in phagocytic macrophages.

Neuropharmacologic properties of pyracetam derivatives

The short duration of ethanol narcosis in the stage of estrus and its longer duration in the stage of diestrus (tD/t 8 > i), the low endogenous ethanol level in the stage of estrus, and the rapid fall in the blood ethanol concentration after administration of a narcotic dose during estrus are thus characteristic of female rats which choose ethanol in preference to water under free choice conditions and consume it in larger doses.

Action of fragments of the cocaine molecule on the CNS

The effect of ecgonine, tropine, tropinone and some of their derivatives, tropane, N-methylpyrrolidine, and N-methylpiperidine on impulse summation in the CNS, the conditioned avoidance reflex, antagonism with hexobarbital, synergism with cocaine, and also their toxicity (LD50) were investigated experimentally. Benzoylecgonine, the methyl ester of ecgonine, ecgonine itself, tropine, pseudotropine, carbomethoxytropinone, tropinone, tropane, N-methylpyrrolidine, and N-methylpiperidine were shown to have a definite stimulating effect on the activity of the CNS and, in this respect, are similar to cocaine. It is concluded that compounds whose molecules contain the structure of tropane or one of its fragments have a central stimulant effect and that the stimulant action of cocaine on the CNS may be associated with the tropane moiety of its molecule.

Synthesis and pharmacological activity of phenothiazine derivatives containing the adamantyl radical

The introduct ion of a bulky and highly lipophilic rad ica l into the molecule of a physiological ly act ive substance leads, in a num ber of ca ses , to a cons iderab le change in the magnitude and c h a r a c t e r of i ts b io logical act ivi ty . This has been shown for compounds which have hypoglycemic [1, 2], c u r a r e l i k e [3, 4, 5], hormona l [6], and o ther f o r m s of pha rmaco log ica l ac t iv i t ies [7]. In th i s connection it was of i n t e re s t to a s ce r t a in how the introduct ion of adarnantyl r ad i ca l s af fec ts the act ivi ty of compounds of the phenothiazine s e r i e s , whose 10-dia lkylaminoalkyl de r iva t ives have neurolept ic p r o p e r t i e s [8], while the 10-d ia lkylaminoacyl de r iva t ives d isplay ac t iv i ty with r e s p e c t to the ca rd iovascu l a r s y s t e m [9].

Azacycloalkanes VIII. Aromatic amides of N-substitutedα-pyrrolidinedicarboxylic acids

In s ea rch of new anes the t ics and, f i r s t of all, for p repara t ions to be used as sur face anes the t ics , as wel l as for the study of the dependence of pharmacologica l act ivi ty on the chemical s t ruc tu re , a synthes is was ca r r i ed out of a roma t i c amides of N-subst i tuted a~-pyrrolidinecarboxylic acids [1]. The in termedia te e s t e r s of N-subst i tuted ~ -pyr ro l id ineca rboxy l i c acids (II) with R =CH 3 or C2H 5 were obtained f rom ~,5dihalovaler ic acids by the method descr ibed by us e a r l i e r [7]. Fo r the synthesis of e s t e r s of amino acids II with heav ie r r e s idues at the ni t rogen atom of the he terocycl ic r ing, it was found convenient to c a r r y out cycl izat ion of ethyl e s t e r of ~ b r o m o 5 c h l o r o v a l e r i c acid {III) with p r i m a r y amines:

New route to the synthesis of octahydropyrrolo[1,2-a]pyrazines

Octahydropyrrol[1,2-a]pyrazines are structural fragments of several drugs [4, 9], the synthesis of which were brought about through the difficultly available chloropentanoic acid using lithium aluminum hydride [1]. In the present work we examine a new route to octahydropyrrolo[1,2-a]pyrazine (Ia) and its homologs, starting form the 3,4-dihydropyrrolo[1,2-a]pyrazines (II), which is easily accessible [5-7]. It was established earlier that the reduction of the azomethine bond in compounds II proceed easily [8], and thus the possibility of the complete hydrogenation of the 3,4-dihydropyrrolo[1,2-a]pyrazine system is defined by the possibility of hydrogenation in this pyrrole ring. We showed that the hydrogenation of IIa with catalysis by precious metals with the formation of Ia proceeds in acidic medium and at room temperature and atmospheric pressure [2].