A SERIES OF ALKOXY)-2-N-METHYL-1,2,3,4-TETRAHYDROISOQUINOLINES - CYSTEINE-REACTIVE MOLECULAR YARDSTICKS FOR PROBING ALPHA(2)-ADRENERGIC RECEPTORS

A series of alkoxy)-2-N-methyl-1,2,3,4-tetrahydroisoquinolines (7a-d) was prepared and characterized as SH-reactive molecular yardsticks use ful in probing az-adrenergic receptors. Rapid displacement of the meth anesulfonyl group by a cysteine residue in dilute aqueous solution wit h concomitant formation of a disulfide conjugate was verified by MALDI -TOF mass spectrometric analysis of the reaction of 7a with a cysteine -containing decapeptide. 7a-d all showed a marked affinity for the thr ee different variants of human alpha(2)-adrenergic receptors: H alpha( 2A)wt, H alpha(2B)wt, and mutant H alpha(2A)Ser201Cys197. However, onl y the mutated receptor (H alpha(2A)Ser201Cys197) was irreversibly inac tivated, and the extent of inactivation in this case was linearly depe ndent on the length of the side chain of 7a-d. These results show that the molecular yardstick approach tested here can provide useful infor mation for modeling receptor proteins.