ABSTRACT
Substituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have been identified as high affinity and selective 5-HT6 antagonists. Compounds from this series had a range of pharmacokinetic profiles in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological profile 2 (SB-357134) was selected for further pre-clinical evaluation.
Subject(s)
Piperazines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Biological Availability , Blood-Brain Barrier/physiology , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Substrate Specificity , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsSubject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Sulfonamides/pharmacology , Thiophenes/pharmacology , Administration, Oral , Animals , Biological Availability , Cell Line , Humans , Rats , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Thiophenes/chemistry , Thiophenes/pharmacokineticsABSTRACT
5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.
Subject(s)
Autoreceptors/antagonists & inhibitors , Piperidones/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Spiro Compounds/pharmacology , Animals , Aspartic Acid/metabolism , Autoreceptors/metabolism , CHO Cells , Cricetinae , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Guinea Pigs , Humans , Hypothermia/chemically induced , Hypothermia/metabolism , In Vitro Techniques , Indoles/toxicity , Male , Models, Molecular , Oxadiazoles/chemistry , Oxadiazoles/metabolism , Oxadiazoles/pharmacology , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Piperidones/chemical synthesis , Piperidones/chemistry , Piperidones/metabolism , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Antagonists/metabolism , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Structure-Activity Relationship , SwineSubject(s)
Cerebral Cortex/physiology , Oxadiazoles/pharmacology , Piperazines/pharmacology , Piperidones/pharmacology , Receptors, Serotonin/physiology , Serotonin Antagonists/pharmacology , Spiro Compounds/pharmacology , Animals , Body Temperature Regulation/drug effects , CHO Cells , Cerebral Cortex/drug effects , Cricetinae , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guinea Pigs , Humans , Oxadiazoles/chemistry , Piperazines/chemistry , Piperidones/chemistry , Receptor, Serotonin, 5-HT1B , Receptors, Serotonin/drug effects , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Serotonin/metabolism , Spiro Compounds/chemistry , Sumatriptan/pharmacology , TransfectionSubject(s)
Indoles/pharmacology , Muscle Contraction/drug effects , Piperidines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Administration, Oral , Animals , Dioxanes/pharmacology , Dogs , Guinea Pigs , Indoles/chemical synthesis , Piperidines/chemical synthesis , Receptors, Serotonin, 5-HT4 , Serotonin Antagonists/chemical synthesis , Structure-Activity Relationship , Sulfonamides/pharmacologySubject(s)
Dioxanes/chemical synthesis , Piperidines/chemical synthesis , Serotonin Antagonists , Serotonin Antagonists/chemical synthesis , Animals , Dioxanes/pharmacology , Guinea Pigs , Metoclopramide/analogs & derivatives , Muscle Contraction/drug effects , Piperidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties. Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d and 8, and imidazo[1,5-alpha]pyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid of either dopamine antagonist or gastric motility stimulatory properties. Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial. From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.