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SEARCH FOR NEW DRUGS ACTOPROTECTOR AND ADAPTOGEN PROPERTIES OF ADAMANTANE DERIVATIVES (A REVIEW)
I. S. Morozov,1 I. A. Ivanova,1 and T. A. Lukicheva2 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 5, pp. 3 – 6, May, 2001. Original article submitted December 6, 2000. In a broad sense, actoprotectors may be defined as drugs preventing a decrease in the working capacity under conditions unfavorable for living and functioning. In contrast to psychomotor stimulants (phenamine, etc.), actoprotectors must not be exhaustive with respect to energy resourses of the organism. The effect of actoprotectors reduces to increasing the efficiency of consuming the energetic substrates and to stimulating recovery processes [1, 2]. Adaptogens are pharmacological preparations increasing the general resistance of the organism to the action of a broad spectrum of factors. The nonspecific adjusting influence of adaptogens upon the functional state of the organism under complicated conditions is eventually manifested by an increase in the initially reduced working capacity [3, 4]. There are different mechanisms of adaptogen action, including effects upon various stages of metabolism, neurogenic and humoral-hormonal regulation, the structure and function of cell membranes, lipid peroxidation processes, etc. The pharmacological classes of both actoprotectors and adaptogens are represented by a relatively small number of commercial preparations. A typical actoprotector is bemithyl [2]; typical adaptogens include the synthetic drug dibazole [4] and some preparations of natural origin based on plant extracts (ginseng, Rhodiola rosea, Eleutherococcus senticosus, Aralia manjurica) or animal tissue extracts (such as pantocrin and rantarin, representing reindeer and sica deer velvet antler extracts, respectively), and some others [3, 5]. There are continuing attempts aimed at increasing the arsenal of preparations possessing such properties [6]. In this context, it would be expedient to consider some possibilities and summarize the results of the search for new compounds possessing actoprotector and adaptogen activity among the derivatives of adamantane. This group of compounds is known to exhibit a very broad spectrum of activity [7 – 10]. Midantane and other structurally similar aminoadamantane derivatives are capable of preventing dysfunction and loss of neurons in various pathological states of the brain, including those related to the action of extremal factors (cerebral hypoxic damage, circulation disorders, and traumas, neural infections and intoxications) and some neurodegenerative disorders (Parkinson’s, Alzheimer’s, and Jakob – Creutzfeldt diseases, Huntington’s chorea, disseminated sclerosis). These disorders are characterized by an excess activation of the mediator systems of exciting amino acids (EAAs) [11 – 13] caused by enhanced lipid peroxidation in the neuron membranes and intracell calcium accumulation. The excess activation of EAA receptors gives rise to a still more enhanced calcium penetration inside the cells followed by calcium release from the intracell pools. This initiates cascade mechanisms accelerating the enzymatic reactions leading to the loss of neurons (endogenous toxicity phenomenon). In was established that midantane and memantine, noncompetitive antagonists of the glutamate receptors of the NMDA subtype (named after the corresponding specific ligand, N-methyl-D-aspartic acid), are capable of retarding or stopping this process. When excited, the NMDA receptors open the ionophore channel admitting calcium inside the cell at an amount 2 – 3 times greater as compared to that for an analogous channel of cholinoreceptors [14]. The NMDA receptor possesses specific binding sites for L-glutamic acid and glycine, as well as allosteric modulator sites (spermidine or polyamine) situated on the neuron membrane. In addition, there are regions for the attachment of magnesium and zinc ions (in the aforementioned ionophore channel) and the binding sites of some other ligands (see below) including phencyclidine. It is the phencyclidine site that interacts with midantane and memantine. Study of the memantine activity revealed some fine details in the interaction of aminoadamantane derivatives with intrachannel phencyclidine binding 235 0091-150X/01/3505-0235$25.00 © 2001 Plenum Publishing Corporation Pharmaceutical Chemistry Journal Vol. 35, No. 5, 2001 1 Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia. 2 All-Russia Center for Medicine of Catastrophes, Ministry of Public Health of the Russian Federation, Moscow, Russia. psychoanaleptics such as phenamine or sydnocarb) is related to its ability to promote dopamine release from the neuronal pools [44], blocking the reverse synaptosomal capture of catecholamines and probably activating dopamine synthesis [43, 45]. Bromantan stimulates the cellular and humoral chains of the (initially reduced) immunoreactivity and normalizes the (initially increased) delayed hypersensitivity reaction [46, 47]. In humans, the drug increases the physical and psychic working capacity, accelerates its recovery, and slows down the fatigue development under both normal and complicated (hypoxia and hyperthermia) conditions [48, 49]. The mechanism of the drug action may be related, in addition to the aforementioned factors, to the antiradical activity and the ability to optimize the ratio of blood glucocorticoids and insulin [50] and increase the blood testosterone level [51]. Chlodantan (ADK-910), exhibiting a broader activity spectrum than bromantan, is an adaptogen capable of protecting the organism against hypoxia, low- and high-temperature, toxic and chemical, and other extremal factors. The effect of chlodantan, in contrast to the action of well known adaptogens, is manifested already after a single administration. The mechanisms of the adaptogen activity of chlodantan are not studied in detail, but one of the most important contributions is due to increase in the stability of cell membranes with respect to unfavorable factors. This is achieved, in particular, by decreasing the rate of overactivated lipid peroxidation processes [43, 52]. Chlodantan also produces an immunostimulant action, which is more pronounced than the analogous effect of bromantan. Bromantan and chlodantan are structurally close substances. These compounds, as well as the aforementioned potential antiparkinsonian drug A-7, possess some structural features in common with the known noncompetitive NMDA receptor channel site blockers such as ketamine, phencyclidine, MK-801, and SKF 10047 [14]. These binding site blockers are capable of preventing and reducing the neuron degeneracy caused by hyperactivation of the NMDA subtype glutamate receptors under unfavorable conditions.