Synthesis, β-adrenergic blocking activity and β-receptor binding affinities of 1-substituted-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalates

• Published in: Farmaco (Società chimica italiana : 1989) 2003-08, Vol.58 (8), p.557-562
• Main Authors: Jindal, Dharam Paul, Coumar, Mohane S, Nandakumar, K, Bodhankar, Subhash Laxmanrao, Purohit, Prasad Gopal, Mahadik, Kakasaheb Ramoo, Bruni, Giancarlo, Collavoli, Elga, Massarelli, Paola
• Format: Article
• Language: English
• Subjects: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Antagonists - chemical synthesis; Adrenergic beta-Antagonists - metabolism; Adrenergic beta-Antagonists - pharmacology; Animals; Aryloxypropanolamines; Atenolol; Atenolol - pharmacology; Binding, Competitive; Electrocardiography - drug effects; Erythrocyte Membrane - drug effects; Erythrocyte Membrane - metabolism; Female; Heart Rate - drug effects; Isoproterenol - pharmacology; Male; Mice; Oxalates - chemical synthesis; Oxalates - metabolism; Oxalates - pharmacology; Propanols - chemical synthesis; Propanols - metabolism; Propanols - pharmacology; Propranolol; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1 - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Thymol; Thymol - chemistry; Thymus Plant - chemistry; Uterus - drug effects; β-Adrenergic blocking activity; β-Adrenergic receptor binding affinity
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(03)00083-1

The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 5) and 1- tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 6) were synthesized from thymol ( 1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 μg/kg, i.v.) and 6 (50 μg/kg, i.v.) antagonized isoprenaline (2 μg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 μg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro β 1- and β 2-adrenergic receptor binding assay using turkey erythrocyte membrane (β 1) and lung homogenate of rats (β 2). Both 5 and 6 showed β-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one β-adrenergic receptor. These results suggest that both the compounds possess non-selective β-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.