ABSTRACT
Clinically effective antimigraine drugs such as Sumatriptan have similar affinity at h5-HT1D and h5-HT1B receptors. In the search for a h5-HT1D-selective agonist as an antimigraine agent, a novel series of 3-(propylpiperazinyl)indoles have been synthesized and evaluated at h5-HT1D and h5-HT1B receptors. This class of compounds has provided subnanomolar, fully efficacious h5-HT1D agonists with up to 200-fold selectivity for the h5-HT1D receptor over the h5-HT1B receptor. Unlike other h5-HT1D-selective series, several propylpiperazines demonstrate good oral bioavailability. The optimum compound was 1-(3-[5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl]propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine (7f) which has excellent selectivity for h5-HT1D receptors over other 5-HT receptor subtypes and good oral bioavailability in three species. Compound 7f has been selected for further investigation as a potential development candidate in the treatment of migraine.
Subject(s)
Indoles/chemical synthesis , Migraine Disorders/drug therapy , Piperazines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Male , Models, Molecular , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.
Subject(s)
Indoles/chemical synthesis , Oxazoles/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Migraine Disorders/drug therapy , Models, Molecular , Oxazoles/chemistry , Oxazoles/metabolism , Oxazoles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipSubject(s)
Piperidines/pharmacology , Pyrrolidines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Humans , Piperidines/chemistry , Piperidines/metabolism , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/metabolism , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Recombinant Proteins/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolismSubject(s)
Migraine Disorders/drug therapy , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/therapeutic use , Administration, Oral , Animals , Biological Availability , Receptor, Serotonin, 5-HT1D , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Species SpecificityABSTRACT
The synthesis and the 5-HT receptor activity of a novel series of N,N-dimethyltryptamines substituted in the 5-position with an imidazole, triazole, or tetrazole ring are described. The objective of this work was to identify potent and selective 5-HT1D receptor agonists with high oral bioavailability and low central nervous system penetration. Compounds have been prepared in which the azole ring is attached through either nitrogen or carbon to the indole. Conjugated and methylene-bridged derivatives have been studied (n = 0 or 1). Substitution of the azole ring has been explored either alpha or beta to the point of attachment to indole. In a series of N-linked azoles (X = N), simple unsubstituted compounds have high affinity and selectivity for 5-HT1D receptors. It is proposed that for good affinity and selectivity a hydrogen bond acceptor interaction with the 5-HT1D receptor, through a beta-nitrogen in the azole ring, is required. In a series of C-linked triazoles and tetrazoles (X = C), optimal affinity and selectivity for the 5-HT1D receptor was observed when the azole ring is substituted at the 1-position with a methyl or ethyl group. This study has led to the discovery of the 1,2,4-triazole 10a (MK-462) as a potent and selective 5-HT1D receptor agonist which has high oral bioavailability and rapid oral absorption. The in vitro activity and the preliminary pharmacokinetics of compounds in this series are presented.
