ChemInform Abstract: Synthesis and 5HT-Receptors Affinity of Some 4-Phenylquinoline Derivatives (original) (raw)
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Journal of Medicinal Chemistry, 2009
The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT 3 receptor (5-HT 3 R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT 3 Rs. The potent 5-HT 3 R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT 3 R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT 3 R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT 3 R in the modulation of cardiac parameters.
Biological & Pharmaceutical Bulletin, 2004
A series of 3-chloroquinoxaline-2-carboxamides were designed and prepared by the condensation of 3chloro-2-quinoxaloylchloride with appropriate Mannich bases of the p-aminophenol in the microwave environment. The synthesized compounds were evaluated for serotonin 3 (5-HT 3) receptor antagonistic activities in longitudinal muscle-myenteric plexus (LMMP) preparation from guinea pig ileum against the 5-HT 3 agonist, 2methyl-5-HT. Compound 3g exhibited comparable 5-HT 3 antagonistic activity (pA 2 6.4) to that of standard antagonist Ondansetron (pA 2 6.9), while the other compounds exhibited mild to moderate 5-HT 3 antagonistic activities.
Novel and Highly Potent 5-HT3 Receptor Agonists Based on a Pyrroloquinoxaline Structure
Journal of Medicinal Chemistry, 1997
The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT 3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT 3 receptor and were able to functionally discriminate the central and peripheral 5-HT 3 receptors, being agonists and antagonists, respectively. In functional studies ([ 14 C]guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT 3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT 3 agonists identified to date that are able to cross the blood-brain barrier.
1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist
Journal of Medicinal Chemistry, 1994
A method was found to synthesize 1-(2,5-dimethoxy-4-(t~uoromethyl)phenyl)-2-a~opropane, 5, and its des-a-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent ~-H T~A /~c agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [12511-3-labeled 5-HT,, sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HTu or 5-HT2c receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HTzc receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HTu receptor as compared to 5-HT. In contrast, 6, the a-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the ~-H T~A receptor. In conclusion, the title compound 5 and its a-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HTu receptor may offer at least a partial explanation for the observed higher in vivo potencies of a-methyl-substituted compounds in this series.
Journal of Heterocyclic Chemistry, 2009
in Wiley InterScience (www.interscience.wiley.com). The addition reaction of lithium reagents to the 4 position of 2-chloropyrimidine or 2-chloroquinazoline followed by oxidation of the resultant dihydro intermediate product is a powerful tool for the synthesis of 4-substituted 2-chloropyrimidines or 2-chloroquinazolines. 4-Vinyl derivatives undergo a conjugate nucleophilic addition across the vinyl group. A nucleophilic displacement of chloride in 4substituted 2-chloropyrimidines or 2-chloroquinazolines by treatment with 4-methylpiperazine provides compounds that are antagonists of the serotonin 5-HT 2A receptor.
Synthesis and characterization of 5,6,7,8-tetrahydroquinoline C5a receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2008
A novel series of substituted 2-aryl-5-amino-5,6,7,8-tetrahydroquinoline C5a receptor antagonists is reported. Synthetic routes were developed that allow the substituents on the tetrahydroquinoline core to be efficiently varied, facilitating determination of structure-activity relationships. Members of the series display high binding affinity for the C5a receptor and are potent functional antagonists.
Archiv der Pharmazie, 2015
In our previous paper, we have reported that some 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic activity for the serotonin 5-HT 1A receptor. In order to examine the influence of the substituent in the position 8 of the purine moiety on the affinity for the serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors, a series of 7-arylpiperazynylalkyl and 7-tetrahydroisoquinolinylalkyl (THIQ) derivatives of 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, functional assays for the 5-HT 1A receptor were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for this receptor.
Bioorganic & Medicinal Chemistry, 2002
Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT 1A ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT 1A and 5-HT 2A receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT 1A receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT 1A ligands (K i =4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT 1A receptors. At the same time, their 5-HT 2A receptor affinity was slightly increased (K i =40-1475 nM), which resulted in a loss of 5-HT 2A /5-HT 1A selectivity. 5-Br,8-OCH 3 derivativethe most potent, mixed 5-HT 1A /5-HT 2A ligand-produced activation of presynaptic 5-HT 1A receptors and showed properties of a 5-HT 2A receptor antagonist. #