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Helmut Buschmann

Publications and source records attributed to Helmut Buschmann.

12 recordsLinked to original sources
PubMed2006

Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways.

1. Two novel selective 5-HT6 receptor ligands E-6801 (6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide) and E-6837 (5-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)naphthalene-2-sulfonamide) were investigated and compared to the putative 5-HT6 receptor antagonists SB-271046 (5-chloro-N-(4-methoxy-3-(piperazin-1-yl)phenyl)-3-methylbenzo[b]thiophene-2-sulfonamide) and Ro 04-06790 (N-(2,6-bis(methylamino)pyrimidin-4-yl)-4-aminobenzenesulfonamide) using a cAMP-mediated pathway. 2. Forskolin stimulation, to increase the magnitude of agonist cAMP responses, and site-directed mutagenesis of the 5-HT6 receptor, in order to yield constitutively active receptor, were applied. 3. 5-HT (E(max), % over basal: 200), E-6801 (120) and E-6837 (23) induced cAMP formation at the rat 5-HT6 receptor. In the copresence of forskolin, cAMP responses were more potent and enhanced to 294 (5-HT, % over forskolin), 250 (E-6801) and 207 (E-6837), respectively. 5-HT-mediated cAMP formation was dose-dependently blocked by SB-271046 (pA(2): 8.76+/-0.22) and Ro 04-6790 (pA(2): 7.89+/-0.10) and not affected by the copresence of forskolin. Both E-6801 and E-6837 yielded partial antagonism of the 5-HT response in the absence of forskolin, whereas antagonism was either completely absent (E-6801) or attenuated (E-6837) in the copresence of forskolin. Intrinsic activity of these 5-HT6 receptor ligands at a constitutively active human S267K 5-HT6 receptor in Cos-7 cells indicated similar efficacy (E(max), % over basal) for 5-HT (97), E-6801 (91) and E-6837 (100), while Ro 04-6790 (-33) and SB-271046 (-39) were equi-efficacious inverse agonists. 4. The use of either forskolin or a constitutively active S267K 5-HT6 receptor enhances the resolution for monitoring the efficacy of 5-HT6 receptor ligands. E-6801 and E-6837 are potent partial agonists at the 5-HT6 receptor. Ro 04-6790 and SB-271046 appear to act as inverse agonists/antagonists.

Animals↗
PubMed2006

Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats.

E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.

Animals↗
PubMed2006

Whole spectrum analysis of ligand efficacy at constitutively active human wild-type and S267K 5-HT6 receptors in HEK-293F cells.

INTRODUCTION: Modulation of constitutive activity by the recombinant wild-type human 5-HT6 receptor was investigated with a series of 5-HT6 receptor ligands by monitoring the cAMP signalling pathway. The impact of the mutation S267K near the B(261)BXXB(265) CIII-loop motif was analyzed on the magnitude of constitutive receptor activity as previously conflicting results have been reported. METHODS: The wild-type 5-HT6 receptor plasmid was obtained by PCR and the mutant S267K5-HT6 receptor was constructed by site-directed mutagenesis and stably transfected in HEK-293F cells by electroporation. The cAMP signalling pathway was monitored as a functional read-out to investigate ligands' responses using homogeneous time resolved fluorescence. RESULTS: Constitutive activity was present both at wild-type and mutant S267K 5-HT6 receptors. Negative efficacy (E(max), % versus basal) as observed at nanomolar concentrations with SB-271046 was larger for mutant (-92+/-1%) than wild-type 5-HT6 receptor (-45+/-1%). Ro 04-6790 also demonstrated negative efficacy at the wild-type 5-HT6 receptor with a magnitude similar to SB-271046 but with a 36-fold lower potency. MS-245 demonstrated at nanomolar concentrations intermediate negative efficacy; -48+/-3% and -16+/-2% at mutant and wild-type 5-HT6 receptor, respectively. The 5-HT-mediated cAMP response was blocked by SB-271046, MS-245 and Ro 04-6790 to their respective level of negative efficacy with pKB values fitting with their binding pK(i) values. E-6801 was a highly potent (pEC50: 10.17 to 10.19) and efficacious agonist (+98 to +102% versus 5-HT) at both wild-type and mutant 5-HT6 receptors. DISCUSSION: The recombinant wild-type human 5-HT6 receptor is constitutively active in HEK-293F cells and displays a high resolution to monitor efficacy properties of 5-HT6 receptor ligands. The resolution capacity to differentiate between efficacy properties of 5-HT6 receptor ligands, in particular for negative efficacy, can be further enhanced by monitoring the mutant S267K 5-HT6 receptor.

Cyclic AMP↗
PubMed2006

Molecular diversity of voltage-gated sodium channel alpha and beta subunit mRNAs in human tissues.

Voltage-gated Na+ channels are composed of one alpha subunit and one or more auxiliary beta subunits. A reverse transcription-polymerase chain reaction assay was used to analyse the expression of the nine known alpha subunits (Na(v)1.1-Na(v)1.9) in 20 different human tissues. The mRNA expression of the currently known beta subunits (beta1, beta2, beta3 and beta4) was also assessed. The mRNAs of voltage-gated Na+ channel alpha and beta subunits were found in a wide variety of human tissues assayed and were present in neuronal and non-neuronal types of cells. These data suggest that, in addition to its well-established role in skeletal muscle, cardiac cells and neurons, voltage-gated Na+ channels might play important, still undetermined local roles in the regulation of cellular functions. These channels could emerge in the next future as potential, new therapeutic targets in the treatment of visceral diseases.

Adult↗
PubMed2006

A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands.

Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.

Animals↗
PubMed2006

Medicinal chemistry strategies to 5-HT(6) receptor ligands as potential cognitive enhancers and antiobesity agents.

Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT(6) receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT(6) receptor by HTS in 1998, several medicinal-chemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further.

Animals↗
PubMed2005

Synthesis of new benzoxazinone derivatives as neuropeptide Y5 antagonists for the treatment of obesity.

Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized and tested for NPY Y5 activity. Most of the compounds were found to be potent and selective NPY Y5 antagonists having nanomolar binding affinities for the NPY Y5 receptor and showing functional antagonism in the forskolin-induced cyclic AMP test. Prelimminary studies in order to understand the structure-activity relationship were undertaken. Selected compounds were further evaluated for in vivo efficacy, affording the lead compound 2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)acetamide 5p, which displayed in vivo activity reducing food intake in rodents.

Animals↗
PubMed2005

Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands.

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.

Adenylyl Cyclases↗
PubMed2002

Photocatalyzed [2 + 2 + 2]-cycloaddition of nitriles with acetylene: an effective method for the synthesis of 2-pyridines under mild conditions.

The photocatalyzed [2 + 2 + 2]-cycloaddition of nitriles with 2 equiv of acetylene to 2-pyridines can be carried out under mild conditions and represents a valuable extension to common synthetical methods. For the ideal wavelength range (350-500 nm), lamps as well as sunlight can be used. Working at room temperature and in organic solvents such as toluene or hexane as well as in water gives satisfying results in many cases. However, it is also possible to vary the solvent and the reaction temperature of the photocatalyzed synthesis and to choose, with respect to the specific substrate, specific requirements for this particular reaction and general requirements of the method. This simple and selective method derives its potential mainly from the large variety of applicable nitriles. Suitable substrates include (functionalized) aliphatic and aromatic nitriles as well as cyanamides derived from secondary amines.

Journal Article↗