Yu. V. Burov

Peptide analogs of pyracetam as ligands for hypothetical nootropic receptors

Pyracetam (N-carbamoylmethylbutyrolactam (I)) is the first representative of nootropic agents, a novel class of psychotropic drugs [18]. Nootropic agents are generally accepted as being drugs which have selective effects on the brain, enhancing the control of the cortex over the subcortical systems and stimulating the higher integrative functions of the brain (thought, attention, and memory) [2]. Pyracetam is used in medicine for improving intellectual and memory function in children with retarded intellectual development [25], to reduce the severity of the psycho-organic syndrome in cerebral changes due to aging [15], and to improve the rate of restoration of memory in patients with traumatic [21] or cerebrovascular [i] disturbances. The nootropic activity of pyracetam is however inadequate [19]. Attempts have been made to increase the effectiveness of pyracetam by structural changes, namely by varying the size of the ring [8], the structure of the side chain [9, i0], and the substituents at the exocyclic nitrogen [12]. A search has been made for a compound with nootropic activity amongst hetero-analogs of pyracetam [ii].

Synthesis and analgesic activity of substituted 1-aryl-2-acylaminoindoles

The N,N-diaryl-N-acylhydrazides (Ia-f) were used as starting compounds. The hydrazides Ia-c were obtained by the reaction of diphenylhydrazine hydrochloride with the anhydride or acid chloride of the acid in the presence of Et3N, and the hydrazides Id-f by the arylation of the corresponding N-aryl-N-acylhydrazides with arylhalides in the presence of CuI and base [2]. The reaction of the hydrazides Ia-f with a small excess of POCI 3 gave the hydrochlorides of the corresponding l-aryl-l-aminoindoles (II) [3].

Synthesis and neurotropic activity of a number of N-[di(n-propyl)acetyl]lactams

Di(n-propyl)acetic (valproic) acid and its derivatives are known to have anticonvulsive [11] and antihypoxic [2] activities. The sodium and calcium salts of valproic acid are among the most active anticonvulsives presently available [12], The great variety of states seen in clinical practice, especially those involving disturbances of cognitive and memory functions in epilepsy, requires the spectrum of the neuropharmacological properties of anticonvulsive agents to be widened. Many of the standard anticonvulsants (benzodiazepines, barbiturates) worsen intellectual and memory functions. The standard nootropic agents (piracetam, aniracetam) lack anticonvulsive activity. This gives a basis for searching for anticonvulsive compounds which do not have adverse effects on memory and, even better, which might improve memory. We report here the synthesis and pharmacological investigation of a number of N-(valproyl)lactams [1, 3], which are of interest because, as new derivatives of valproic acid, they are also acyllactams. We might therefore expect these compounds to have new pharmacological properties which may be useful in the treatment of nervous diseases. N-di(n-propyl)acyllactams (I-III) were synthesized by the interaction of pyrrolidone, piperidone, or hexahydroazepinone with di(n-propyl)acetyl chloride.

Pikamilon-a new vasoactive and nootropic preparation

It has therefore been suggested that a combination of nicotinic acid and GABA in the same molecule would potentiate the action of each component. Compound nicotinoyl-~-aminobutyric acid was first synthesized at the All-Union Vitamin Research Institute in 1970 [ii], and in the subsequent years the product pikamilon, created on its basis, has been widely studied both experimentally and clinically. Pikamilon, a sodium salt of N-nicotinoyl-~-a minobutyric acid, is a white crystalline odorless and hygroscopic powder, readily soluble in water. It was shown when the research had only begun that the compound passes rapidly through the BBB. The essential role of GABA in the central and peripheral regulation of the cerebral circulation [4, 14, 15, 17] and also the presence of a nicotinic acid residue possessing vasoactive properties, determined the priority given to the study of the cerebrovascular properties of pikamilon. In experiments on animals pikamilon had a positive action on the cerebral circulation and also exhibited the properties of a tranquilizer with stimulating component [7]. The action of the compound on the cerebral circulation and on its nervous regulation was studied in experiments on anesthetized cats, on conscious, unrestrained cats, and on unanesthetized rabbits. Pikamilon was shown to stimulate the cerebral circulation and to lower vascular tone in both arterial systems of the brain. The increase in the blood supply to the brain in conscious animals took place to a more marked degree than in cats under general anesthesia. The drug also lowered the blood pressure. It must be emphasized that these effects were manifested after both intravenous and peroral administration of the compound. In anesthetized cats, pikamilon in a dose of i0 mg/kg, given by intravenous injection, increased the blood flow by 28 x7f 3%, but when given internally -- by 18 x7f 1.7%; in conscious animals it was increased by 63 x7f 10% and the effect lasted 120-150 min. The increase in the blood flow in unanesthetized rabbits was 42 x7f 7.3% by Intravenous injection and 24 x7f 8% by the peroral route. In the strength and duration of its cerebrovascular effect, pikamilon is much superior both to GABA and to nicotinic acid. Under the same experimental conditions GABA in a dose of i0 mg/kg (intravenously) caused no change in the cerebral bloodflow, and only when given in a dose of 300 mg/kg did it increase the blood flow into the brain by 20 x7f 2.9%, the effect lasting 3-5 min. Nicotinic acid, also in large doses (50-100 mg/kg) increased the cerebral blood flow temporally on average by 5-10%. In its effect on the cerebral circulation, in comparative experiments pikamilon was more effective than papaverine, nialamide, complamin (xantinol nicotinate), and dihydroergotoxin (redergin). An essential role in the mechanism of action Of pikamilon is played by its effect on nervous control of the cerebral circulation. It weakens changes in the cerebral blood flow during the vasomotor reflex, considerably inhibits constrictor responses of vessels of the

Synthesis and study of the influence of certain products of serotonin metabolism, β-carbolines and related compounds, on the voluntary consumption of alcohol in animals

It is suggested that certain natural serotonin metabolites [i], as well as their cyclic analogs, representing compounds of the group of 8-carbolines, may play a substantial role in processes of formation and manifestation of alcohol dependence, since they intervene in the regulation of alcohol consumption [2, 3], beingproducts of ~n u~uo cyclization of serotonin and its metabolites with acetaldehyde -a metabolite of ethanol [4]. The incorporation of these compounds into the mechanism of formation of alcohol dependence may be determined by their ability to intervene in certain neurochemical processes [4], in particular, the serotoninergic processes. Moreover, the high affinity for the benzodiazepine receptor [5] suggests possible intervention of the compounds under consideration in the emotional processes associated with the attraction to alcohol.

EFFECT OF AMIRIDINE ON CONDITIONED REFLEX IN RATS WITH DAMAGED HIPPOCAMPUS

It is shown that even after partial damage to the hippocampus in male rats by quinolinic acid, which causes selective degeneration of hippocampal neurons, their conditioned reflex to time remains impaired for a period of several months. Treatment with amiridine improves the learning of time-interval estimation by such rats and promotes compensatory/restorative processes in the brain. The brain contains a great diversity of connections, and their stimulation may offer an opportunity for enhancing the operation of compensatory/restorative mechanisms in it.

Synthesis and pharmacological properties of a pyrrole-based heterocyclic prostaglandin analog

As a continuation of our studies [2, 6] fom the purpose of finding new potential platelet aggregation inhibitors among heterocyclic prostaglandin (PG) analogs, we synthesized the heretofore unreported compound 4-bromo-2-(trans-3-oxooctene-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (I) and tested its effect on platelet aggregation as well as on cardiovascular (arterial pressure AP) and nervous system (orientation reflex OR) activity.

The Importance of Some CNS Peptides in the Development of Experimental Alcoholism

The neurochemical mechanisms of ethanol’s action have not yet been fully explored. Various authors have shown that ethanol affects neurotransmitter accumulation, adenylcyclase activity (Kalant, 1975), NaK-ATPase (Kalant, 1981), the enzymes of catecholamine metabolism (Carlson et al., 1973) and transmission processes (Tewari, 1981). There is reason to suppose that the effects of acute and possibly chronic treatment with alcohol could be mediated by alterations in the physico-chemical properties of biological membranes. In fact, ethanol has been shown to increase the mobility of layers in cell membrane (Goldstein et al., 1981) and to produce changes in the activity of membrane-bound enzymes. It also alters the conformation of receptor complexes situated on nerve cell membranes and the disposition of neurotransmitters in the synapses (Ciofalo, 1980). The broad spectrum of ethanol’s effects means that considerable difficulties are encountered when identifying cause and effect relationships in the various disturbances produced by alcoholism. It may be argued that of its many effects on various systems within the organism, this biologically active compound exerts its strongest influence on emotions.

Endocrine Factors in the Pathogenesis of Experimentally-induced Alcoholism

The development of experimentally-induced alcoholism is generally attended by pronounced evidence of endocrinopathy. Peptide and steroid hormones so involved are widely recognized as joint regulators of various forms of animal and human behavior, apart from their more specific functions. Such considerations go a long way towards explaining the abundance of etiological and pathogenetic “endocrine” theories which link a certain illness with ethanol-induced dysfunction of a) peripheral hormone-producing organs, such as gonads, adrenals, thyroid and pancreas and b) those acting centrally, such as pituitary and hypothalamus (Sze, 1977; Van Thiel, 1980; Greene and Hollander, 1980). Endocrine research, as applied to the problem of experimentally-induced alcoholism, follows two basic lines of approach. The first consists of studying the changing pattern of concentration and function of hormones with different chemical structures during the creation of the alcoholism model. The second involves analyzing the effects of hormones and their derivatives on the differing effects of ethanol — on, for example, the voluntary ethanol consumption of experimental animals, or the buildup of tolerance and physical dependence when ethanol is administered chronically.

The Role of Catecholamines and Serotonin in the Formation and Maintenance of Susceptibility to Alcohol

No simple explanation has yet been offered of how the seroto-ninergic and noradrenergic systems function in alcohol dependence. Pharmacological studies on the involvement of these systems in the regulation of voluntary alcohol consumption have failed in this respect. Investigations of the effect of ethanol on the two systems, whether administered chronically or acutely, have given contradictory results, moreover. As described previously (Burov et al., 1981), we were able to sort cross-bred rats into those susceptible or not susceptible to alcohol, according to how long the effects of this narcotic were maintained. This enabled us to explore differences between the animal’s inborn characteristics, concentrating on metabolic, neurochemical, hormonal and behavioral systems.