title: The twin drug approach for novel nicotinic acetylcholine receptor ligands.
abstract: The association of two pharmacophoric entities generates so-called 'twin drugs' or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with α4β2(∗) nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N,N-dimethyl-2-(pyridin-3-yloxy)ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the 'twin' compound. 'Twin' compounds with identical or non-identical entities using the 'no linker mode' or 'overlap' mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the α4β2(∗) nAChR subtype (Ki=0.188 nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono- or difluoro-phenyls. The 'twin drug' approach proved to provide compounds with high affinity and subtype selectivity for α4β2(∗) nAChRs.
authors.affiliation: Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tomassoli
authors.affiliation: Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA. Electronic address: danielag@hawaii.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
mesh_terms: D000818:Animals; D019281:Dimerization; D015195:Drug Design; D008024:Ligands; D051379:Mice; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2
keywords: 3D QSAR pharmacophore; Nicotinic acetylcholine receptor; Structure–activity relationship; Twin drugs; nAChR