ABSTRACT
A series of potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists based on 1-thia-4,7-diaza-spiro[4.4]nonane-3,6-dione motif has been disclosed. Enantiomers of potent racemate compound 8a (K(i) = 26 nM) displayed difference in activity (K(i) of 15 nM versus 855 nM) signaling the influence of the stereochemistry of the chiral center on potency. In addition, the potent enantiomer displayed significant selectivity in biological activities over several related family members.
Subject(s)
Benzazepines/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Spiro Compounds/chemistry , Thiazolidines/chemistry , Benzazepines/chemical synthesis , Benzazepines/metabolism , Humans , Protein Binding , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited â¼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
Subject(s)
Brain/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Animals , Dogs , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Molecular Structure , Rats , Receptors, Serotonin , Serotonin Antagonists/pharmacokinetics , StereoisomerismABSTRACT
7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.
Subject(s)
Benzofurans/chemistry , Piperidines/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/pharmacology , Animals , Brain/embryology , Brain/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Memory, Short-Term/drug effects , Models, Chemical , Rats , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
Dimebolin (Dimebon), is a non-selective antihistamine approved in Russia for the treatment of allergy. Recently, this drug has been shown to be neuroprotective in cellular models of Alzheimer's disease and Huntington's disease, and to preserve cognitive function when chronically administered to AF64A lesioned rats. Interests in identifying the molecular targets of dimebolin have intensified with reports of efficacy in clinical trials with Alzheimer's patients. Dimebolin has been found to interact with a number of molecular targets including acetylcholinesterases, N-methyl-d-aspartate receptors, and voltage-gated calcium channels, with potencies in the range of 5-50 microM. In the present study, the action of dimebolin at the serotonin 5-HT(6) receptor was investigated. Dimebolin binds with moderate affinity to both the human and rat recombinant 5-HT(6) receptor (K(i)=26.0+/-2.5 nM and 119.0+/-14.0 nM respectively) as well as the native rat 5-HT(6) receptor, and acts as an antagonist in functional cAMP assays. Furthermore, dimebolin occupies the 5-HT(6) receptor in vivo as assessed by ex vivo autoradiography, with a dose-occupancy relationship similar to that of the selective 5-HT(6) antagonist SB-399885. Finally, both SB-399885 and dimebolin produce an acute enhancement of short-term social recognition memory, although dimebolin is approximately 10-fold less potent than SB-399885. Taken together, these studies demonstrate that dimebolin antagonizes the 5-HT(6) receptor with higher affinity than other targets characterized to date, and suggest that this activity may play a role in the acute cognition enhancing effects of this compound in preclinical models and in the clinic.
