Pharmacology of oxazolidinones in rat decerebrate rigidity, with reference to their glutamate blocking action

Abstract

A newly synthesized compound, 5-[N-benzyl-N-(3piperidinopropyl)]amino3-phenylisoxazole (MLV208) (Fig. I) has a powerful inhibitory action on the glutamate response at the crayfish neuromuscular junction (NMJ) where glutamate is thought to be an excitatory neurotransmitter. In addition, MLV-208 has an inhibitory action on anaemic decerebrate rigidity in rats and drug-induced tremor in mice (Shinozaki and Hirate, 1986). The neuromuscular system of the crayfish has some properties in common with mammalian central synapses, and provides us with an insight into the chemical transmission processes at many synapses as it can be used as a model for studying the mechanism of action of drugs on synaptic transmission in the mammalian central nervous system (CNS). The experimental finding that the compound significantly depressed the decerebrate rigidity in rats as well as the glutamate response at the crayfish NMJ, therefore, gave us a hint to invent a new class of the CNS depressants. MLV-208 contains a constituent moiety of alkylenediamine which is contained in some CNS depressants. We were particularly interested in the structure of trimethylenediamine. Among many test samples of alkylenediamine derivatives, some oxazolidinones and aminoalcohols, which were synthesized on the base of the structure-activity relationship in drug design, demonstrated a potent inhibitory action on rat decerebrate extensor rigidity and the glutamate response in the invertebrate NMJ and the mammalian central neurons. A compound, which has a hexamethylene-iminopropyl group and an isobutyl group at the 3and 4-position of the oxazolidinone ring, respectively, has so far been the most powerful in reducing the severity of the anaemic decerebrate rigidity. The potency of reducing the rigidity was changed to some extent by replacing the terminal imino group with various other tertiary amines and significantly altered by replacing the isobutyl group at the 4-position with other alkyl groups. Thus, we have been interested in two trimethylenediamine compounds, in particular an oxazolidinone, 4-(2-methylpropyl)3-[3-(perhydroazepin1-yl)propyl]5-phenyl1,3-oxazolidin-2-one (MLV-6976) and an aminoalcohol, 5-methyllphenyl2(3-piperidinopropylamino)hexane-l-ol (MLV-5860) (Fig. 1). Decerebrate rigidity is a condition which appears when the brain stem of an animal is transected or damaged above the vestibular nuclei which exert a strong facilitatory action on ipsilateral extensor motoneurones. Animals with decerebrate rigidity have proved useful for the study of the mechanisms of action of the centrally acting muscle relaxants and some CNS depressants (Maxwell and Read, 1972; Sontag and Wand, 1973; Maxwell and Sumpter, 1974; Fukuda et al., 1974; Anderson and Raines, 1976; Wand et al., 1977; Ochiai and Ishida, 1982; Goto et al., 1982, 1983; Raines et al., 1985; Masaki