Stereospecific effects of benzo[d]isothiazolyloxypropanolamine derivatives at beta-adrenoceptors: synthesis, chiral resolution, and biological activity in vitro.
We performed the asymmetric synthesis of four enantiopure benzo[d] isothiazo-3-or 5-yloxypropanolamine derivatives, previously described as competitive antagonists at beta-adrenoceptors. The chemical characterization of each enantiomer was accomplished by (1)H NMR and HPLC/DAD/CD. The direct chromatographic separation of the enantiomers via chiral HPLC was investigated. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). The enantiomers obtained had enantiomeric purities suitable for biological assays. Tested in isolated rat cardiac and intestinal tissues to evaluate their effects at beta(1)- and beta(3)-adrenoceptors, the (S)-enantiomers revealed a higher degree of antagonism than (R)-enantiomers at both subtypes, even though their activity was greater at the cardiac beta(1)-subtype. The potent and cardiospecific antagonistic effect exerted by the compounds tested suggests that the benzisothiazole moiety could be an interesting scaffold for discovering new chiral beta-blocking drugs.
Pharmaceutical Department, School of Pharmacy, University of Parma, Parma, Italy.
Mara
M
Comini
Cristina
C
Pozzoli
Matteo
M
Incerti
Daniela
D
Rossi
Simona
S
Collina
Ornella
O
Azzolina
Elena
E
Di Vittorio
Giovanni
G
Morini
Enzo
E
Poli
D018674:Adrenergic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D018674:Adrenergic Antagonists; D011412:Propanolamines; D013844:Thiazoles