ABSTRACT
Central nervous system (CNS) selective amino acid transporters provide an important function in maintaining tonic extracellular levels of amino acids that act as neurotransmitters, synaptic modulators or neurotransmitter precursors. Small molecule inhibitors of these transporters have been postulated and in some cases demonstrated to be useful in the treatment of a range of CNS driven disorders such as epilepsy, anxiety, psychosis, depression, pain and neurodegenerative disease. Although much of the research to date in this field has focussed on inhibition of the gama-amino butyric acid (GABA) transporters more recent reports have also generated interest in modulation of glycine, glutamate and proline transporters. This article will review the current medicinal chemistry literature and structure activity relationships known for mammalian CNS selective amino acid transporters.
Subject(s)
Amino Acids/metabolism , Brain/metabolism , Carrier Proteins/antagonists & inhibitors , Central Nervous System Agents/pharmacology , Animals , MammalsABSTRACT
Analogues of the antimalarial pentaquine, 1, in which the nature of the side-chain on the 8-amino position was varied, were prepared and evaluated for anticoccidial activity both in vitro and in vivo. Specifically, both the inter-nitrogen distance and the nature of the terminal amino group were investigated. Novel analogues of equal or improved efficacy in vitro and in vivo to pentaquine were discovered.
Subject(s)
Aminoquinolines/pharmacology , Coccidiostats/pharmacology , Aminoquinolines/chemistry , Animals , Chickens , Coccidiostats/chemistry , Eimeria/drug effects , Structure-Activity RelationshipABSTRACT
During a chemistry program aimed at finding a novel analogue of pentaquine with improved in vivo activity, a number of hypotheses concerning the way this drug acts in the chicken were investigated. Consideration of the products of monoamine oxidase metabolism of pentaquine suggested that pentaquine aldehyde is the likely active metabolite. Although isolation of this unstable compound was not possible, oxime and cyclic acetal and ketal derivatives were obtained and shown to possess in vitro anticoccidial activity.
Subject(s)
Aminoquinolines/pharmacology , Coccidiostats/pharmacology , Aminoquinolines/antagonists & inhibitors , Aminoquinolines/chemistry , Animals , Cattle , Cells, Cultured , Chickens , Coccidiostats/antagonists & inhibitors , Coccidiostats/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/pharmacologyABSTRACT
Carbocyclic analogues of the antibacterial natural product frenolicin B have been synthesised. These analogues were active against parasitic protozoa of the genus Eimeria and represent a new series of anticoccidial agents. The synthesis of simplified analogues helped to define a possible pharmacophore for frenolicin.
