ISSN:0365-6233    

DOI:10.1002/ardp.19953280702

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19953280703

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractWe have been able to show that the most important 5‐HT2aantagonists and agonists, belonging to chemically diverse classes can be fitted accurately into a common pharmacophoric pattern. In this paper we make use of the developed pharmacophore models to construct a fragmental amino acid model reflecting binding properties and affinity data of the structures under study. The proposed fragment model is then superimposed onto the transmembraneous part of the 5‐HT2areceptor. For this purpose the helix coordinates from the known structure of bacteriorhodopsin serve as a matrix. New structures with high affinity for the 5‐HT2asites were designed and their biological activities were predicted on the basis of interaction energies calculated with the fragment model. The predicted data show excellent agreement with experimental binding affin

ISSN:0365-6233    

DOI:10.1002/ardp.19953280704

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractAlicyclic ester analogues of the gastroprokinetic benzamide metoclopramide (1) and its ester congener SDZ 205557 (2), a 5‐HT4receptor antagonist, were prepared byO‐alkylation of 4‐amino‐5‐chloro‐2‐methoxybenzoate withN‐(2‐chloroethyl) substituted alicyclic amines. The bromo and iodo analogue of compound13b(2‐(1‐piperidinyl)ethyl 4‐amino‐5‐chloro‐2‐methoxybenzoate) were obtained by halogenation of dechloro‐13bwithN‐halogenated succinimides. The series was evaluated in functionalin vitroassays with regard to affinity for serotoninergic 5‐HT4, 5‐HT3and muscarinic M3receptors. The affinities for 5‐HT4and M3receptors were below 6.0 (pKBor pA2). On 5‐HT4receptors in guinea‐pig ileal longitudinal muscle and rat oesophagus, the majority of compounds revealed partial 5‐HT4receptor agonism susceptible to blockade by SDZ 205557, a reference 5‐HT4receptor antagonist (pKb= 7.25 − 7.73 (guinea‐pig ileum) and 7.09 — 7.43 (rat oesophagus)). The relative agonist potency was in the range of 5 – 303 % (5‐HT: 100 %). Compound13band its bromo analogue17were the most potent esters of the series. The enantiomers of13g((R)‐ and (S)‐2‐(2‐methyl‐1‐piperidinyl)ethyl 4‐amino‐5‐chloro‐2‐methoxybenzoate) interacted stereoselectively with 5‐HT4receptors and displayed enantiomeric potency ratios (R)/(S) of 4.3 — 8.7. There was an excellent correlation between (a) antagonist affinity on guinea‐pig ileum and rat oesophagus, (b) relative agonist potency on guinea‐pig ileum and rat oesophagus, and (c) between antagonist affinity and relative agonist potency within each assay (r2>0.91). The new compounds may serve as academic tools in evaluating the functional role of 5‐HT4receptors. The selective partial 5‐HT4receptor agonists presented in this paper may be useful to restore physiological motility and secretion in the gut with reduced or

ISSN:0365-6233    

DOI:10.1002/ardp.19953280705

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractThe diastereomeric 1‐(fluoro/difluorophenyl)‐2‐phenylethylenediamines (4‐fluoro:erythro‐1/threo‐1; 2,4‐difluoro:erythro‐2/‐threo‐2; 2,6‐difluoro:erythro‐3/threo‐3) and the diastereomeric 1‐(4‐fluorophenyl)‐2‐(3‐hydroxyphenyl)ethylenediamines (erythro‐4/‐threo‐4) were synthesized from appropriately substituted stilbenes by reaction with IN3and subsequent LiAlH4reduction. Coordination of the 1,2‐diphenylethylenediamines to platinum was carried out by use of K2PtI4. The water‐soluble aquasulfatoplatinum(II) complexes (erythro/threo‐1‐PtSO4‐erythro/threo‐4‐PtSO4) were obtained from the diiodoplatinum(II) complexes by reaction with Ag2SO4. Additionallyerythro/threo‐4‐PtSO4anderythro/threo‐4‐PtSO4were transformed into the dichloroplatinum(II) complexes (erythro/threo‐1‐PtCl2,erythro/threo‐4‐PtCl2) by treatment with KCl. In contrast to the less effectiveerythro‐configurated sulfatoplatinum(II) complexes thethreo‐analogues showed comparable or even superior activities to cisplatin on the human MDA‐MB‐231 breast cancer cell line. On the MXT‐M‐3.2 breast cancer of the mouse onlyerythro‐ andthreo‐4‐PtSO4caused similar effects like cisplatin. The strong inhibitory effect of the diastereomeric sulfatoplatinum(II) complexes on the P‐388 leukemia of the mouse was equal to that of cisplatin. On the latter

ISSN:0365-6233    

DOI:10.1002/ardp.19953280706

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractThe 5‐HT1Areceptor affinities and ionization constants of a set of 1‐arylpiperazine (4) 1,2,3,4‐tetrahydroisoquinoline (6), and ‐quinoline (7) containingN‐(ω‐arylalkyl) orN‐(E)‐cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5‐HT1Aligands equipotentto 1‐phenylpiperazine (4a) and 1,2,3,4,4a5‐hexahydropyrazino[1,2‐a]indole (5). On the basis of molecular modelling studies it was also demonstrated that6c, 6dand8amimicked very well the reference structures of4aand its rigid analog5. Another, more complex 1,2,3,4‐tetrahydroisoquinoline derivative3, which served as a model compound to confirm the previously reported 5‐HT1Abinding mode of derivatives1a–dand2, had the highest 5‐HT1Aaffinity (Ki= 6.7 ± 0.5 nM)

ISSN:0365-6233    

DOI:10.1002/ardp.19953280707

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractThe novel aminobenzindolone8was prepared and evaluated as a potential antipsychotic agent. The target compound was synthesized in eight steps starting from the tetrahydrobenzindolone9. The key step of the synthesis was an electrophilic amination of the aromatic ketone11followed by reductive degradation when the diethoxymethyl group was employed for protection of the lactam nitrogen and also for the benzylic position 2a. Dopamine and serotonin receptor binding studies revealed8to be a potent and selective ligand at the D‐2 autoreceptor (ki= 4.0 nM). Furtherin vivostudies including the GBL‐test and locomotor activity measurements indicated agonistic activity of8at the prejunctional binding sites. Comparison ofab initiobased molecular electrostatic isopotential maps corroborates our hypothesis that the dopamine structure6, containing an intramolecular hydrogen bond donating effect of themeta‐HO‐group, represents the conformation which is active at the dopamine D‐2 aut

ISSN:0365-6233    

DOI:10.1002/ardp.19953280708

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractThe possibility of the preparation of some ester derivatives of dimethylxanthines from 1‐theobromine‐ and 7‐theophylline acetic acids and 7‐(2‐hydroxyethyl)‐theophylline by DCC/DMAP‐mediated esterification under mild conditions was studied. The structures of the compounds synthesized and by products isolated were demonstrated by microanalyses, UV‐, IR‐, and1H NMR data. Acute toxicity assessment of the compounds on mice showed that compounds4, 5, 6, and7are less toxic than aminophylline. A pharmacological study of thein vitrobroncholytic effect (IC50and pD2values) of the derivatives and aminophylline showed that the new compound4(1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7H‐purine‐7‐acetic acid 2‐(1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7H‐purine‐7‐yl)ethyl ester) has a strong bronchodilating effect on serotonine‐ and acetylcholine‐induced spasm in guinea pig trachea. The same compound does not influence barbiturate — induced hypnosis and locomotor activity, unlike to t

ISSN:0365-6233    

DOI:10.1002/ardp.19953280709

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractResolution of (RS)‐tetrindole (3) and enantioselective reductions of the imine7yielded (S)‐(+)‐(4) and (R)‐(−)‐tetrindole (5). The absolute stereochemistry of4was established by X‐ray analysis of the corresponding Mosher amide6. Fromin vitroas well asin vivodata (MAO‐inhibiton, levels of monoamines and their respective metabolites in rat brain),4was identified

ISSN:0365-6233    

DOI:10.1002/ardp.19953280710

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractNew 1‐phenyl‐ and 1‐(3‐chlorophenyl)piperazines containing a 4‐[3‐(heterocyclic)propyl] fragment were synthesized. It was found that of all the investigated compounds11b(Ki= 13 ± 2 nM) and8b(Ki= 38 ± 2 nM) were the most active 5‐HT1Aand 5‐HT2Aligands, respectively. Several derivatives (3a, 4a, 8b, 11b, 12b, 13a, and13b) were selected as good candidates for new, potential antidepressants on the basis of their 5‐HT1A/5‐HT2Arece

ISSN:0365-6233    

DOI:10.1002/ardp.19953280711

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY