Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists

A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.     

5-HT3 receptor antagonists

The 5-HT₃ receptor is a ligand-gated ion channel widely distributed in the central and peripheral nervous systems. Many selective 5-HT₃ receptor antagonists have been developed; animal studies with such compounds suggested their potential therapeutic value in combating emesis and a wide range of CNS diseases including anxiety, schizophrenia, drug dependence and Alzheimer’s disease. Their successful introduction as anti-emetics, with irritable bowel syndrome emerging as a further indication have partially fulfilled this initial promise. However, the CNS area has been less productive and, to date, no selective 5-HT₃ receptor antagonist has been approved for use in a CNS disease.     

5-HT3受体阻滞剂帕洛诺司琼

帕洛诺司琼（palonosetron）是新型5-HT3受体阻滞剂,适用于中～重度呕吐化疗所引起的恶心、呕吐,其与传统5-HT3受体阻滞剂相比,具有疗效高、作用时间长、用量小、不良反应少的优点.现对帕洛诺司琼的作用机制、药动学、安全性以及临床应用等做一简单综述.     

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option

A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent–child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantly worse (p=0.007). The case-control analyses revealed a nominal significant association of the HTR3D variant rs1000592 (p.H52R) with OCD (p=0.029) which was also evident after combination of the case-control and the trio-results (p=0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR3C was significantly associated with OCD (p=0.007). The association findings of the HTR3C and the HTR3E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR3A-E genes in OCD and OCD-related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR3E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction.     

5-HT(3) receptor antagonists

The 5-HT(3) receptor is a ligand-gated ion channel widely distributed in the central and peripheral nervous systems. Many selective 5-HT(3) receptor antagonists have been developed; animal studies with such compounds suggested their potential therapeutic value in combating emesis and a wide range of CNS diseases including anxiety, schizophrenia, drug dependence and Alzheimer's disease. Their successful introduction as anti-emetics, with irritable bowel syndrome emerging as a further indication have partially fulfilled this initial promise. However, the CNS area has been less productive and, to date, no selective 5-HT(3) receptor antagonist has been approved for use in a CNS disease.     

Pharmacological properties of a novel class of 5-HT3 receptor antagonists.

The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.     

Anxiolytic potential of 5-HT3 receptor antagonists.

The 5-HT3 receptor antagonists such as ondansetron have been shown to have anxiolytic-like activity in a wide range of preclinical tests: in the mouse black: white test, the rat social interaction test, the rat elevated X-maze and the marmoset human threat test. Ondansetron, like other 5-HT3 receptor antagonists appears to have important advantages over existing anxiolytic therapies. Thus, the 5-HT3 receptor antagonists are not sedative, they do not have addictive liabilities, there are no problems of withdrawing from chronic treatment and they can be used following benzodiazepine withdrawal. Such compounds even inhibit the behavioural syndrome associated with withdrawal from drugs of abuse, nicotine, alcohol, cocaine, opiates. The preclinical data, therefore, indicates the 5-HT3 receptor antagonists as novel anxiolytics of the future, and there is new clinical work in support of this suggestion.     

Value of 5-HT3 receptor antagonists, particularly as anti-emetic drugs]

Several binding sites for serotonin or 5-hydroxytryptamine (5-HT) were identified by using selective agonists and antagonists. Today, 5-HT3 receptor types are considered to occupy a critical position in the emetic pathway. The discovery of 5-HT3 receptor antagonists originated from metoclopramide, an antidopaminergic drug introduced in France 25 years before as a modifier of digestive motricity; it represents a therapeutic advance, since it led to the first class of antiemetic drugs specifically designed to prevent severe cytotoxic drugs-evoked emesis and devoid of noticeable side-effects. It must be emphasized upon the necessity of developing new experimental tests in living animals and performing controlled trials on patients under chemotherapy to achieve this progress.     

5-Chloroindole: a potent allosteric modulator of the 5-HT3 receptor

Background and Purpose

The 5-HT₃ receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT₃ receptor.

Experimental Approach

5-HT₃ receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT₃A receptor and also the mouse native 5-HT₃ receptor that increases neuronal contraction of bladder smooth muscle.

Key Results

Cl-indole (1–100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT₃A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT₃ receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT₃A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT₃ receptors. In contrast to its effect on the 5-HT₃ receptor, Cl-indole did not alter human nicotinic α7 receptor responses.

Conclusions and Implications

The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT₃ receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT₃ receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.

Linked Articles

Recent reviews on allosteric modulation can be found at:Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476-5381.2012.02223.xRoche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231     

Emerging differences between 5-HT3 receptor antagonists.

A brief review is presented of some recently described 5-HT3 receptor antagonists. These antagonists are primarily targeted for use as anti-emetics. However, evidence is emerging that there are differences in their basic pharmacology. This evidence is reviewed in terms of the selectivity of the antagonists in binding studies and also of their efficacy in emesis and gastric emptying. The possibility that these differences may translate into meaningful clinical differences between the available 5-HT3 receptor antagonists in their use as anti-emetics is also discussed.     

Advances in use of the 5-HT3 receptor antagonists

Nausea and vomiting continue to rank as important side effects for cancer patients receiving chemotherapy. The class of drugs known as the 5-HT3 receptor antagonists have become widely used for chemotherapy-induced nausea and vomiting, and are considered a standard part of care for moderately- and highly-emetogenic chemotherapy in combination with corticosteroids. Ondansetron (Zofran, Glaxo Wellcome), granisetron (Kytril, SmithKline Beecham) and dolasetron (Anzemet, Hoechst Marion Roussel) are commercially available in the US. Intravenous forms of all three drugs have demonstrated efficacy in preventing acute (< or = 24 h following chemotherapy) nausea and emesis due to moderately- and highly-emetogenic chemotherapy. Oral forms of the drugs have been shown to be effective in prevention of nausea and emesis due to moderately-emetogenic chemotherapy. More recently, oral 5-HT3 receptor antagonists have demonstrated efficacy in the prevention of nausea and vomiting due to highly-emetogenic chemotherapy as well. Comparative trials between the three agents have shown no clinically important differences in outcome and they should be considered clinically equivalent. Optimal oral anti-emetic regimens for high-dose chemotherapy with bone marrow or stem cell transplantation remain to be determined and future oral studies should target this population. In general, the decision of which 5-HT3 receptor antagonist to select for formulary inclusion should be based on the dose of anti-emetic used and the acquisition cost of the agents being compared. The oral route should be used whenever possible.     

5-HT3 receptor antagonists attenuate cocaine-induced locomotion in mice

The 5-HT3 receptor antagonists ICS 205-930 and zacopride attenuated cocaine-induced locomotor activity in C57BL/6ByJ mice. In contrast, the aselective 5-HT1 and 5-HT2 receptor antagonist, methysergide did not affect the response to cocaine. The effect of the 5-HT3 receptor antagonists was not due to general sedation, because zacopride did not alter the locomotor response to caffeine.     

New benzimidazole derivatives: selective and orally active 5-HT3 receptor antagonists

The synthesis of new 5-HT(3) receptor antagonists is an interesting field of research because of their wide therapeutic use. The aim of this work is to functionally characterise a new series of benzimidazole derivatives previously described. These compounds bind to 5-HT(3) receptors and have been evaluated using in vitro (rat tunica muscularis mucosae) and in vivo tests (Bezold-Jarisch reflex in rat and gastrointestinal motility and spontaneous motility in mice). Ondansetron and 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenil)methyloxy]-3-[1-[2-methylsulfonylamino]piperidin-4-yl]propan-1-one hydrochloride (RS 39604) were used as well known 5-HT(3) and 5-HT(4) receptor antagonists. These benzimidazole derivatives have proved to be 5-HT(3) receptor antagonists. Interestingly, they are as active as ondansetron when they are intraperitoneally (i.p.) or orally (p.o.) administered and, in mice, they seem to induce fewer behavioural changes at similar effective doses than does ondansetron. The present results confirm the usefulness of the previously proposed pharmacophore and justify the interest in these new benzimidazole derivatives.     

5-HT7 receptor antagonists as a new class of antidepressants

It is now admitted that major depression is associated with monoaminergic dysfunctions as well as with functional brain plasticity impairments. Despite the wide variety of medications available to treat such a syndrome, two foremost problems still remain unresolved: one-third of patients do not respond to any treatment and there is an unwanted 2-4 week delay in the onset of therapeutic action of all available antidepressant drugs. These issues draw attention to the need and urgency to develop more efficacious treatments and to accelerate the antidepressant response. The combination of an atypical antipsychotic, known to be a potent 5-HT(7) receptor antagonist, with an antidepressant has been recently proposed as an alternative therapy. Hence, blockade of 5-HT(7) receptors might represent a key determinant for this hastening strategy. This review summarizes recent data that put emphasis on the putative antidepressant properties of selective 5-HT(7) receptor antagonists. The use of such ligands seems very promising to elaborate novel generations of antidepressants that surpass the efficacy and onset of action limitations of existing antidepressants.     

Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides.

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.     

Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists

A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.