Pharmacological receptors of nematoda as target points for action of antiparasitic drugs

Abstract

Cholinergic receptors of parasitic nematodes are one of the most important possible sites of action of antiparasitic drugs. This paper presents some of our own results of electrophysiological and pharamcological examinations of nicotinic and muscarinic receptors of nematodes, as well as data from literature on a new class of anthelmintics that act precisely on cholinergic receptors. The nicotinic acetylcholine receptor (nAChR) is located on somatic muscle cells of nematodes and it is responsible for the coordination of parasite movement. Cholinomimetic anthelmintics act on this receptor, as well as acetylcholine, an endogenic neurotransmitter, but they are not sensitive to enzyme acetylcholineesterase which dissolves acetylcholine. As opposed to the nicotinic receptor of vertebra, whose structure has been examined thoroughly, the stoichiometry of the nicotinic receptor of nematodes is not completely known. However, on the grounds of knowledge acquired so far, a model has been constructed recently of the potential composition of a type of nematodes nicotinic receptor, as the site of action of anthelmintics. Based on earlier investigations, it is supposed that a conventional muscarinic receptor exists in nematodes as well, so that it can also be a new pharamocological target for the development of antinematode drugs. The latest class of synthesized anthelmintics, named aminoacetonitriles (AAD), act via the nicotinic receptor. Monepantel is the first drug from the AAD group as a most significant candidate for registration in veterinary medicine. Even though several groups of cholinomimetic anthelmintics (imiodazothiazoles, tetrahydropyrimidines, organophosphat anthelmintics) have been in use in veterinary practice for many years now, it is evident that cholinergic receptors of nematodes still present an attractive place in the examinations and development of new antinematode drugs. .

Holinergički receptori parazitskih nematoda jedno su od najznačajnijih mogućih mesta delovanja antiparazitskih lekova. U ovom radu prikazani su neki od rezultata elektrofizioloških i farmakoloških ispitivanja nikotinskog i muskarinskog receptora nematoda, kao i literaturni podaci o novoj klasi antihelmintika koji deluju upravo na holinergičke receptore. Nikotinski acetilholinski receptor (nAChR) se nalazi na somatskim mišićnim ćelijama nematoda i odgovoran je za koordinaciju kretanja parazita. Holinomimetički antihelmintici deluju na ovaj receptor kao i acetilholin, endogeni neurotransmiter, ali nisu osetljivi na enzim acetilholin-esterazu koja razlaže acetilholin. Za razliku od nikotinskog receptora vertebrata, čija je struktura dobro ispitana, stohiometrija nikotinskog receptora nematoda nije u potpunosti poznata. Međutim, u skorije vreme na osnovu dosadašnjih saznanja konstruisan je model potencijalnog sastava jedne vrste nikotinskog receptora nematoda, kao mesta delovanja antihelmintika. Na osnovu ranijih istraživanja postoji pretpostavka da klasični muskarinski receptor postoji i kod nematoda, tako da i on može biti novo farmakološko ciljno mesto za razvoj antinematodnih lekova. Najnovija klasa sintetisanih antihelmintika, nazvana aminoacetonitrili (AAD), deluje preko nikotinskog receptora. Monepantel je prvi lek iz grupe AAD kao najznačajniji kandidat za registraciju u veterinarskoj medicini. Iako se u veterinarskoj kliničkoj praksi već duži niz godina primenjuje nekoliko grupa holinomimetičkih antihelmintika (imiodazotiazoli, tetrahidropirimidini, organofosfatni antihelmintici), očigledno je da holinergički receptori nematoda i dalje predstavljaju atraktivno mesto u ispitivanju i razvoju novih antinematodnih lekova.