A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties.

We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.

Classification of dopamine, serotonin, and dual antagonists by decision trees.

Dopamine antagonists (DA), serotonin antagonists (SA), and serotonin-dopamine dual antagonists (Dual) are being used as antipsychotics. A lot of dopamine and serotonin antagonists reveal non-selective binding affinity against these two receptors because the antagonists share structurally common features originated from conserved residues of binding site of the aminergic receptor family. Therefore, classification of dopamine and serotonin antagonists into their own receptors can be useful in the designing of selective antagonist for individual therapy of antipsychotic disorders. Data set containing 1135 dopamine antagonists (D2, D3, and D4), 1251 serotonin antagonists (5-HT1A, 5-HT2A, and 5-HT2C), and 386 serotonin-dopamine dual antagonists was collected from the MDDR database. Cerius2 descriptors were employed to develop a classification model for the 2772 compounds with antipsychotic activity. LDA (linear discriminant analysis), SIMCA (soft independent modeling of class analogy), RP (recursive partitioning), and ANN (artificial neural network) algorithms successfully classified the active class of each compound at the average 73.6% and predicted at the average 69.8%. The decision trees from RP, the best model, were generated to identify and interpret those descriptors that discriminate the active classes more easily. These classification models could be used as a virtual screening tool to predict the active class of new candidates.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

Frovatriptan: a selective type 1B/1D serotonin receptor agonist for the treatment of migraine headache.

Frovatriptan belongs to an innovative family of compounds aimed at breaking through the long-standing barrier of migraine headache understanding and treatment. While a typology of headaches has been recognized for some time, and a number of therapies have been introduced for reduction of headache pain and duration, the causes of migraine remain a subject of debate. Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation. Frovatriptan, like all the triptans, acts by inducing vasoconstriction of the meningeal arteries. It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin 5-HT1B/1D receptors. Frovatriptan has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials, which have also indicated that dose adjustments for age or gender are not necessary for the drug. Patients have found the use of frovatriptan acceptable over the long-term, and overall a low-incidence of adverse effects has been reported. Though not a prophylactic, frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine.

Drug therapy options for patients with irritable bowel syndrome.

Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation.

Effect of different 5-hydroxytryptamine receptor subtype antagonists on the micturition reflex in rats.

OBJECTIVE: To evaluate the effects of antagonists of different subfamilies of 5-hydroxytryptamine (5-HT) receptors on bladder function in anaesthetized and conscious rats. MATEERIALS AND METHODS: The urinary bladder of female anaesthetized rats was catheterized urethrally and filled with physiological saline until spontaneous bladder contractions occurred. Infravesical pressure was measured by a pressure transducer and displayed continuously on a chart recorder. The time of bladder quiescence (to the disappearance of rhythmic contractions) after injection with different compounds tested was recorded. Conscious rats underwent cystometry with chronically (infravesical) implanted catheters to continuously record bladder capacity (evaluated as amount of saline infused between voiding cycles) and maximal voiding pressure. The affinity for the human recombinant serotoninergic 5-HT1A subtype (inhibition of specific binding of [3H]8-hydroxy-2-(di-n-propylamino) tetralin) and the effects on the [35S]guanosine 5'-(gamma-thio) triphosphate (GTPgammaS) binding in HeLa cells was also evaluated. RESULTS: Among the compounds tested, only 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethyl-piperazine (p-MPPI) and methiothepin showed nanomolar affinity for the 5-HT1A receptors, the former being a neutral antagonist and the latter an inverse agonist in the [35S]GTPgammaS binding model. Intravenous injection of low doses of p-MPPI and methiothepin induced a dose-dependent disappearance of isovolumic bladder contractions in anaesthetized rats (> 10 min). At the highest doses, the dose-response curves were bell-shaped. The amplitude of bladder contractions was not markedly altered. The tested antagonists of 5-HT2, 5-HT3, 5-HT4, and 5-HT6 serotoninergic subtypes were poorly active or inactive in the model. Similarly, these compounds were inactive on cystometry in conscious rats, whereas p-MPPI and methiothepin induced a consistent increase in bladder capacity. Methiothepin also decreased the voiding pressure, whereas p-MPPI did not affect this variable. CONCLUSIONS: These findings confirm that only selective 5-HT1A receptor antagonists have favourable effects on the bladder, inducing an increase in bladder capacity with no derangement of bladder contractility.

Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat.

Although accumulating evidence suggests that serotonergic drugs are able to substitute for the ethanol (EtOH) cue in rats, it is still unclear which 5-HT receptor subtypes are responsible for this phenomenon, and whether these receptors are critically involved in the EtOH cue. In the present study, rats were trained to discriminate EtOH (1000 mg/kg, i.p., t-15 min) from saline in a two-lever food-reinforced procedure, and it was investigated to which extent serotonergic compounds with a certain level of specificity for either 5-HT1B, 5-HT2A or 5-HT2C receptors generalized to the EtOH cue. Subsequently, the involvement of these receptor subtypes was ascertained by the use of selected 5-HT receptor antagonists. The 5-HT1B receptor agonist CP 94,253 (0.3-5 mg/kg, i.p.) and the mixed 5-HT(2C/1B) receptor agonist mCPP (0.1-1 mg/kg, i.p.), but not the preferential 5-HT2A receptor agonist DOI (0.3-1 mg/kg, i.p.), completely generalized to the EtOH cue. Complete generalization of the former two compounds coincided with a decrease in response rate. In antagonism studies, it was shown that the 5-HT1B receptor antagonist GR 127935 (10 mg/kg, i.p.) completely blocked generalization of CP 94,253 to the EtOH cue, suggesting that stimulation of 5-HT1B receptors produces discriminative stimulus effects which are similar to those of EtOH. GR 127935 (10 mg/kg, i.p.), as well as the mixed 5-HT(1B/2C) receptor antagonist metergoline (1 mg/kg, i.p.), and the 5-HT2C receptor antagonist SB 206,553 (1 mg/kg, i.p.) completely blocked generalization of mCPP to the EtOH cue. This suggests that 5-HT1B and 5-HT2C receptors are required for the generalization of mCPP to the EtOH cue. The present findings indicate that activation of 5-HT1B and 5-HT2C, but not of 5-HT2A receptors, mimics the EtOH cue. However, the finding that neither metergoline, nor the 5-HT2A receptor antagonist MDL 100,907 blocked the EtOH cue, suggests that these receptors play only a minor role in the discriminative stimulus effects of a moderately low dose of EtOH.

Serotonin receptors and therapeutics.

Since its discovery, serotonin (5-hydroxytryptamine = 5-HT) has become a major player on the neurotransmitter "stage". Multiple receptor subtypes for 5-HT have been identified and classified, and a vast pharmacology of 5-HT has emerged. In particular, 5-HT has been shown to exert marked effects on the cardiovascular system, central nervous system (CNS) and gastrointestinal (GI) tract, and important ligands have been developed that mimic or block its action selectively. Furthermore, drugs that release 5-HT, and others that prevent its uptake, have been developed. This brief review focuses on the pharmacology of 5-HT agonists and antagonists that exhibit, at least partly, clinical relevance.

Progress in controlling emesis with cancer chemotherapy.

Marked progress in supportive care in cancer, and in control of chemotherapy-induced emesis in particular, has been accomplished over the past several years. Several effective antiemetic agents and regimens have been tested and are widely available. Emesis due to chemotherapy can now be completely controlled in the majority of patients. Progress in both clinical trials and in neuropharmacology has resulted in a new class of agents, the serotonin antagonists. These agents have an excellent therapeutic index and are well suited for a variety of clinical settings. Problems remain especially in the control of delayed emesis, in patients given several days of chemotherapy, and in radiation-induced emesis. Achieving the best antiemetic control, and at the same time having cost-effective therapy, is an ongoing challenge.

Molecular modeling of 5-HT3 receptor ligands.

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.