title: A series of 6-(omega-methanesulfonylthioalkoxy)-2-N-methyl- 1,2,3, 4-tetrahydroisoquinolines: cysteine-reactive molecular yardsticks for probing alpha2-adrenergic receptors.
abstract: A series of 6-(omega-methanesulfonylthioalkoxy)-2-N-methyl-1,2,3, 4-tetrahydroisoquinolines (7a-d) was prepared and characterized as SH-reactive molecular yardsticks useful in probing alpha2-adrenergic receptors. Rapid displacement of the methanesulfonyl group by a cysteine residue in dilute aqueous solution with 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 three different variants of human alpha2-adrenergic receptors: H alpha(2A)wt, H alpha(2B)wt, and mutant H alpha(2A)Ser201Cys197. However, only the mutated receptor (H alpha(2A)Ser201Cys197) was irreversibly inactivated, and the extent of inactivation in this case was linearly dependent on the length of the side chain of 7a-d. These results show that the molecular yardstick approach tested here can provide useful information for modeling receptor proteins.
authors.affiliation: Department of Chemistry, University of Turku, Finland. petri.heinonen@utu.fi
authors.forename: P
authors.initials: P
authors.lastname: Heinonen
authors.forename: K
authors.initials: K
authors.lastname: Koskua
authors.forename: M
authors.initials: M
authors.lastname: Pihlavisto
authors.forename: A
authors.initials: A
authors.lastname: Marjamäki
authors.forename: V
authors.initials: V
authors.lastname: Cockcroft
authors.forename: J M
authors.initials: JM
authors.lastname: Savola
authors.forename: M
authors.initials: M
authors.lastname: Scheinin
authors.forename: H
authors.initials: H
authors.lastname: Lönnberg
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes / Q000138:chemical synthesis*; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000145:classification; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013439:Sulfhydryl Reagents / Q000138:chemical synthesis
chemical_list: D007546:Isoquinolines; D015335:Molecular Probes; D010455:Peptides; D018341:Receptors, Adrenergic, alpha-2; D013439:Sulfhydryl Reagents; C058525:2-methoxyidazoxan; D003545:Cysteine; D019329:Idazoxan