title: Molecular alliance-from orthosteric and allosteric ligands to dualsteric/bitopic agonists at G protein coupled receptors.
abstract: Cell-membrane-spanning G protein coupled receptors (GPCRs) belong to the most important therapeutic target structures. Endogenous transmitters bind from the outer side of the membrane to the "orthosteric" binding site either deep in the binding pocket or at the extracellular N-terminal end of the receptor protein. Exogenous modulators that utilize a different, "allosteric", binding site unveil a pathway to receptor subtype-selectivity. However, receptor activation through the orthosteric area is often more powerful. Recently there has been evidence that orthosteric/allosteric, in other words "dualsteric", hybrid compounds unite subtype selectivity and receptor activation. These "bitopic" modulators channelreceptor activation and subsequent intracellular signaling into a subset of possible routes. This concept offers access to GPCR modulators with an unprecedented receptor-subtype and signaling selectivity profile and, as a consequence, to drugs with fewer side effects.
authors.affiliation: Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.forename: Jens
authors.initials: J
authors.lastname: Schmitz
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled