title: Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists.
abstract: Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)). A number of compounds with good antagonist potencies against the alpha(2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha(2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha(2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.
authors.affiliation: Juvantia Pharma Ltd, Lemminkäisenkatu 5, FI-20520 Turku, Finland.
authors.forename: Iisa P J
authors.initials: IP
authors.lastname: Höglund
authors.forename: Satu
authors.initials: S
authors.lastname: Silver
authors.forename: Mia T
authors.initials: MT
authors.lastname: Engström
authors.forename: Harri
authors.initials: H
authors.lastname: Salo
authors.forename: Andrei
authors.initials: A
authors.lastname: Tauber
authors.forename: Hanna-Kaisa
authors.initials: HK
authors.lastname: Kyyrönen
authors.forename: Pauli
authors.initials: P
authors.lastname: Saarenketo
authors.forename: Anna-Marja
authors.initials: AM
authors.lastname: Hoffrén
authors.forename: Kurt
authors.initials: K
authors.lastname: Kokko
authors.forename: Katariina
authors.initials: K
authors.lastname: Pohjanoksa
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.forename: Juha-Matti
authors.initials: JM
authors.lastname: Savola
authors.forename: Siegfried
authors.initials: S
authors.lastname: Wurster
authors.forename: Oili A
authors.initials: OA
authors.lastname: Kallatsa
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000634:Aminoquinolines; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins