Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.

A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.

The present studies have identified a series of aminotriazines as novel 5-HT7 receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT7 receptor and do not bind to either the 5-HT2C or 5-HT6 receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist. (C) 2004 Elsevier Ltd. All rights reserved.

A series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. From this series of benzoxazole derivatives, compounds 14 and 17 were identified as melatonin receptor agonists.

A series of 4-substituted anilides with human melatonergic affinity is reported. Butyramides 26, 39, 42, 52, 57, and 58 all demonstrated subnanomolar MT(2) binding affinity and MT(2) selectivity of at least 70-fold over the MT(1) receptor. Compound 26 demonstrated full agonism at the MT(2) receptor.

A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.

A series of chiral heterocyclic aminopyrrolidine derivatives was synthesized as novel melatoninergic ligands. Binding affinity assays were performed on cloned human MT1 and MT2 receptors, stably expressed in NIH3T3 cells. Compound 16 was identified as an orally bioavailable agonist at MT1 and MT2 melatonin receptors with low vasoconstrictive activity.

Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT2 receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT2 agonist, which produces advances in circadian phase in rats at doses of 1–56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.

This chapter analyzes the pharmacologlcal interventions in the sleep process. Insomnia is the term used to describe difficulties in initiating sleep, maintaining sleep, or obtaining a restorative sleep. It is a symptom that can arise for a multitude of reasons and represents a significant public health problem. About 40% of the individuals suffering from insomnia attempt to self-medicate with over-the-counter agents or alcohol, indicating that a clear need still exists for accepted, effective medications. Because the likelihood of severe or chronic insomnia increases with age, the management of insomnia in the geriatric population is also a significant concern. The benzodiazepines (BZs) remain the mainstay of hypnotic therapy. The BZs produce their effects by acting at benzodiazepine receptors (BZRs) that are allosteric modulatory sites of the GABAA receptor. The chapter overviews current research aimed at improved pharmacological intervention in the sleep process and discusses the concepts related to GABAA benzodiazepine receptor ligands and melatonin receptor ligands. Aenosine receptor ligands are described and an overview of histamine receptor ligands is also presented.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The petrosins are a family of marine alkaloids that includes the chiral, racemic isomer petrosin (1), the meso isomer petrosin A (2), and the chiral, scalemic isomer petrosin B (3). Monte Carlo molecular mechanics calculations indicated that petrosin (1) is the most stable isomer of the group, suggesting that it might be synthesized by a route that utilizes thermodynamic control for establishing the relative configurations of the eight stereocenters. The model synthesis summarized in Scheme 1 showed that intramolecular Mannich condensation is a viable route to the quinolizidone subunit of the petrosins and that this synthesis gives isomer 5, having the relative configuration found in petrosin and petrosin A, as the kinetic product. Equilibration studies with this isomer afforded an approximate equimolar mixture of 5 and diastereomer 6, having the relative configuration found in one of the two quinolizidone milts of petrosin B. On the basis of this model study, a "stereo-uncontrolled" synthesis of petrosin was carried out, as summarized in Schemes 3-5. The key step of this synthesis is a "double-barrelled" intramolecular Mannich condensation of a diamino keto dialdehyde. This transformation provides crystalline petrosin in 23% yield, along with about 37% of a mixture of petrosin diastereomers. Although simple acid- and Lewis acid-mediated equilibrations of this mixture of diastereomers were not successful, the derived mixture of bis-butylimines undergoes equilibration upon treatment with protic acid to give a mixture that is greatly enriched in petrosin, relative to the other isomers. Crystallization of this equilibration mixture provided another 10% of petrosin, bringing the overall yield of petrosin to 33%. In the course of the equilibration studies, pure samples of petrosin A (2), petrosin B (3), and petrosin B' (7) were isolated and characterized.

The synthesis and amino acid pharmacology of twelve N-substituted quinoxalinediones is reported. In particular, compounds 4a and 4b show significant antagonism at both the AMPA and glycine-site NMDA receptors. The functional antagonism of 4a has been demonstrated.

A new method, the addition of N-benzyloxychloroformate to methyl anthranilate followed by base-catalyzed cyclization, has been employed to synthesize the N-hydroxyquinazolinedione 1 and heterocyclic derivatives. N-Benzyloxycarbonylimidazole is a useful synthon to prepare N-hydroxyureas.