Potent 5-HT6 Receptor Antagonists Research Articles

Synthesis and biological evaluation of benzoisothiazole derivatives possessing N,N-dimethylformimidamide group as 5-HT6 receptor antagonists

A series of novel N,N-dimethyl-N′-(5-(Ar-sulfonamido) benzo[d]isothiazol-3-yl)formimidamides was designed and synthesized as 5-HT6 ligands. Here N,N-dimethyl formimidamides was used as a replacement for an aminoethyl moiety. In vitro functional assays demonstrated compounds 9b and 9i significantly inhibited the 5-HT-induced Ca2+ increases (9b; IC50=0.36μM and 9i; IC50=0.44μM), indicating that 9b and 9i were potent 5-HT6 receptor antagonists. Compounds 9i also showed good selectivity on the 5-HT6 over 5-HT4 and 5-HT7 receptors.

Synthesis and pharmacological evaluation of aryl aminosulfonamide derivatives as potent 5-HT6 receptor antagonists

A series of novel aryl aminosulfonamides was designed and synthesized as 5-HT6 receptor ligands. Many compounds screened in a functional reporter gene based assay displayed potent antagonistic activity with Kb values in the range of 0.02–10nM. The lead compound 11m exemplified in this series showed good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. The compound was selected for detailed profiling.

8-Sulfonyl-substituted tetrahydro-1H-pyrido[4,3-b]indoles as 5-HT6 receptor antagonists

A series of novel 8-sulfonyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles (THPI) has been synthesized and their ability to interact with 5-HT6 receptors evaluated in cell-based and radioligand binding assays. Amongst evaluated THPIs, compounds 9.HCl and 20.HCl have been identified as the most potent 5-HT6 receptor antagonists with Ki values equal to 2.1nM and 5.7nM and IC50 values (functional assay) equal to 15nM and 78nM, respectively. Affinities of these two compounds for several serotonin receptors in the competitive radioligand binding assays as well as their specificity profiles against a panel of therapeutic targets have been determined.

P2-478: Discovery and in vivo evaluation of potent 5-HT6 receptor antagonists for cognition enhancement in treating Alzheimer's disease

5-HT6 receptors are expressed in the brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. We report the development of a novel, aqueous-soluble, safe, BBB penetrant potent series of small molecule antagonists of 5-HT6 receptors in a series of new Dimebon analogs. Recently Dimebon was reported to have met all five efficacy endpoints in a one-year randomized, double-blind, placebo-controlled phase II study of ∼200 patients with mild to moderate Alzheimer's Disease. We were the first to show that Dimebon is a potent 5-HT6 antagonist (Ki = 70 nM) and selected this drug as a starting point for the design of novel drug-like chemotypes. The design, synthesis, and SAR studies included tri- and bicyclic “core” and/or “decoration” variations of chemical structure in several consecutive iterations. Cognition disorders perhaps due to their unique intricacy have not benefited from rational single-targeted drug design. In response to this challenge we have selected a few key biotargets for specific modulation. The “constellation” of 5-HT6, 5-HT2C, AChE, Ca L-channel, NMDA, etc. was chosen as desirable for inhibition (antagonism), and hERG, 5-HT2B (“black holes”) were identified as undesirable. SAR data will be demonstrated around the lead series to illustrate the improvements in targeting affinities at multiple biomolecules. Hit-to-lead optimization of this series has led to the discovery of the advanced lead compounds possessing the desired fingerprint along with a promising in vivo profile. The lead compounds demonstrated an excellent PK-PD correlation. Administering these agents has significantly reversed scopolamine- and MK801-induced deficit in a rodent novel object recognition paradigm and passive avoidance test. The compounds have also reversed the deficit in water maze spatial learning compared to vehicle-treated scopolamine-matched controls. These studies provide further support for the potential therapeutic utility of 5-HT6 receptor antagonists possessing a desired fingerprint in disorders characterized by cognitive deficits such as Alzheimer's Disease.

Antibodies and Antisense Oligonucleotide for Probing the Distribution and Putative Functions of Central 5-HT6 Receptors

Among the recently cloned serotonin (5-hydroxytryptamine, 5-HT) receptors, the 5-HT6 subtype is of special interest for at least two reasons: 1) it is abundant in limbic areas which participate in the control of mood and emotion; and 2) some antidepressants and antipsychotics are potent 5-HT6 receptor antagonists. Studies using polyclonal anti-5-HT6 receptor antibodies and an antisense oligonucleotide were performed in order to investigate further the function(s) of 5-HT6 receptors in the rat brain. Immunocytochemistry at the light and electron microscope levels showed that 5-HT6 receptors are mainly confined to the dendritic compartment, suggesting that they could mediate 5-HT actions on neuronal firing. In some limbic areas, 5-HT6 receptor-like immunoreactivity is also associated with neuronal cilia with yet unknown functions. Continuous i.c.v. infusion with an antisense oligonucleotide for 3–4 days resulted in decreased 5-HT6 receptor-like immunostaining of the nucleus accumbens and anxiogenic behaviours in the social interaction and elevated plus maze tests. Selective 5-HT6 receptor ligands are eagerly expected to investigate further the potential implication of these receptors in limbic-dependent behaviours.