Human α1-adrenoceptor subtype selectivity of substituted homobivalent 4-aminoquinolines

A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human α(1)-adrenoceptor (α(1)-AR) subtypes and the human serotonin 5-HT(1A)-receptor (5-HT(1A)-R). We find that the structure-specificity profiles are different for the two series at the α(1)-AR subtypes, which suggests that homobivalent 4-aminoquinolines can be developed with α(1)-AR subtype selectivity. The 8-methyl (8-Me) ethyl-linked analogue has the highest affinity for the α(1A)-AR, 7 nM, and the greatest capacity for discriminating between α(1A)-AR and α(1B)-AR (6-fold), α(1D)-AR (68-fold), and the 5-HT(1A)-R (168-fold). α(1B)-AR selectivity was observed with the 6-methyl (6-Me) derivative of the ethyl- and heptyl-linked 4-aminoquinoline dimers and the 7-methoxy (7-OMe) derivative of the heptyl-linked analogue. These substitutions result in 4- to 80-fold selectivity for α(1B)-AR over α(1A)-AR, α(1D)-AR, and 5-HT(1A)-R. In contrast, 4-aminoquinoline dimers with selectivity for α(1D)-AR are more elusive, since none studied to date has greater affinity for the α(1D)-AR over the other two α(1)-ARs. The selectivity of the 8-Me ethyl-linked 4-aminoquinoline dimer for the α(1A)-AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the α(1B)-AR, makes them promising leads for drug development of α(1A)-AR or α(1B)-AR subtype selective ligands with reduced 5-HT(1A)-R affinity.