67449-41-6Relevant articles and documents
Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor
Deyrup,Nowicki,Richards,Otero,Harrison,Baker
, p. 168 - 177 (2007/10/03)
Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2- yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k(off), estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K(i) and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (-)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenylethyl and isopropyl had higher k(off)-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k(off)- and K(i)-values). In addition, replacement of the 8- hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k(off). Only those derivatives with the lowest k(off)-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR.
5-[1-HYDROXY-2-(SUBSTITUTED-AMINO)]ETHYL-8-HYDROXY-CARBOSTYRIL DERIVATIVES
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, (2008/06/13)
5-[Hydroxy-2-(substituted-amino)]ethyl-8-hydroxy-carbostyril derivatives represented by the formula (I) STR1 wherein R 1 and R. sup.2, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group containing a straight or branched chain alkyl moiety having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 6 carbon atoms, or R 1 and R. sup.2 may, when taken together with the nitrogen atom to which they are attached, form a 5 or 6-membered substituted or unsubstituted heterocyclic ring containing 1 or 2 nitrogen, oxygen or sulfur atoms as hetero atoms, the pharmaceutically acceptable acid addition salts thereof and a process for preparing the above compounds.
