Improvement in the Selectivity and Metabolic Stability of the Serotonin 5-HT1A Ligand, S 15535: A Series of cis- and trans-2-(Arylcycloalkylamine) 1-Indanols was written by Peglion, Jean-Louis;Goument, Bertrand;Despaux, Nicole;Charlot, Valerie;Giraud, Helene;Nisole, Christian;Newman-Tancredi, Adrian;Dekeyne, Anne;Bertrand, Marc;Genissel, Patrick;Millan, Mark J.. And the article was included in Journal of Medicinal Chemistry in 2002.SDS of cas: 746638-33-5 The following contents are mentioned in the article:
S 15535 (1) displays a distinctive profile of agonist and antagonist (weak partial agonist) activity at pre- and postsynaptic 5-HT1A receptors, resp. It has proven to be active in several models predictive of anxiolytic, antidepressant, and procognitive properties. In an attempt to increase its selectivity and metabolic stability, and guided by the results of human metabolic studies, we prepared a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols. Irresp. of the nature of the arylcycloalkylamine moiety or the presence of substituents on the indanol ring, trans isomers invariably showed the highest affinity for human, recombinant h5-HT1A receptors. Among them, compounds 39, 42, 45, 49, 52, 53, 54, 57, 61, 64, 67, and 70 displayed similar or higher affinity than the parent compound 1 (pKi ≥ 9.1). Lack of selectivity toward α1-adrenoceptors has been frequently encountered with 5-HT1A ligands. While S 15535 itself presents reasonable selectivity (158-fold) in this respect, trans piperazine derivatives 4-trans, 35, 39, 41, 47, 64, 68, 69, 70, 71 displayed even more pronounced selectivity vs α1-adrenoceptors, with the nitro derivative 70 being highly selective (1259-fold). However, among the set of trans piperidines prepared, only 64, which also bears a nitro on the indanol ring, displayed selectivity greater than the parent compound 1. All trans derivatives behaved as partial agonists at h5-HT1A receptors, as determined by their submaximal stimulation of [35S]GTPγS binding to a level comparable to that observed with S 15535. In metabolic stability studies in vitro using human microsomes and hepatocytes, only trans piperazines and, in particular, 35, 39, 41, 68, 69, and 70, showed an improvement relative to 1, whereas trans piperidines did not. Compounds 35, 39, 41, and 70, which combined both improved selectivity and metabolic stability, and which retained the distinctive pharmacol. characteristics of S 15535, were evaluated in animal models of anxiety. Of these, 35, which showed the highest oral bioavailability in vivo in rats, was resolved into its two isomers 36 and 37. The eutomer 37 displayed 47% oral bioavailability in the rat and was potently active (0.1-0.5 mg/kg, s.c.) in the rat ultrasonic vocalization and social interaction models, predictive of anxiolytic activity. In conclusion, 2-(arylcycloalkylamine) 1-indanols represent a novel class of potent 5-HT1A ligands in which the presence of the hydroxyl group in the benzylic position enhances selectivity, while substituents on the Ph ring of the indanol moiety improve both selectivity and metabolic stability. This study involved multiple reactions and reactants, such as 8-Bromo-6-fluorochroman (cas: 746638-33-5SDS of cas: 746638-33-5).
8-Bromo-6-fluorochroman (cas: 746638-33-5) belongs to organobromine compounds. Bromo compounds are employed in a variety of metal-catalyzed coupling reactions. They are also ideal candidates for the synthesis of Grignard reagents that have wide-applicability in organic synthesis. alpha-Bromoesters are employed in the Reformatsky reaction for the synthesis of beta-hydroxyesters. Bromine-containing agents predominate because not only are they more efficient than similar chlorine-containing species, but also the high atomic weight of bromine ensures that it is present in a high mass fraction within most organobromine compounds.SDS of cas: 746638-33-5
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary