ABSTRACT
Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Piperidines/pharmacology , Receptors, Serotonin, 5-HT1/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Quantum Theory , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.
Subject(s)
Leiomyoma/drug therapy , Ovary/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Drug Design , Estrogens/blood , Female , Humans , Models, Chemical , Ovary/metabolism , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/chemistry , Software , Structure-Activity RelationshipABSTRACT
This is the first report for secondary metabolites in an African medicinal plant, Pachyelasma tessmannii (Leguminosae). Four novel saponins, pachyelasides A-D, were isolated from the methanol extract of the root bark by using recycling HPLC. These compounds showed molluscicidal activity (LD(50) < or =8.0 mug/mL) against the South American snail, Biomphalaria glabratus. The structures were determined on the basis of extensive nuclear magnetic resonance spectroscopic and matrix-assisted laser desorption/ionization time-of-flight mass spectrometric studies.
Subject(s)
Biomphalaria/drug effects , Fabaceae/chemistry , Saponins/isolation & purification , Saponins/pharmacology , Triterpenes/isolation & purification , Triterpenes/pharmacology , Animals , Plant Extracts/chemistry , Plant Roots/chemistry , Saponins/chemistry , Triterpenes/chemistryABSTRACT
Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and 'inverted' indazole provided more potent and selective 5-HT1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT1F receptor agonists, and the 5-HT1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT1F receptor recognition.
Subject(s)
Benzamides , Bridged Bicyclo Compounds, Heterocyclic , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Binding, Competitive , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Evaluation Studies as Topic , Molecular Structure , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Receptor, Serotonin, 5-HT1FABSTRACT
Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.
