Determinants of action of hydrophobic amines on ASIC1a and ASIC2a.
Acid-sensing ion channels (ASICs) are involved in numerous physiological and pathological processes in the central nervous system. Development of pharmacological tools capable to inhibit or potentiate these channels is important for our knowledge about roles of ASICs in the neuronal network and can be promising for treatment of some disorders. Recently we described four hydrophobic monoamines that potentiate and inhibit ASICs depending on subunit composition of the channel and peculiarities of the drug structure. In the present work we performed structure-activity relationship analysis using derivatives of adamantane, phenylcyclohexyl and 9-aminoacridine to reveal the main determinants of action of amine-containing compounds on recombinant ASIC1a and ASIC2a homomers expressed in CHO cells. We found that the most active compounds are monocations with protonatable aminogroup. In general, potentiators and inhibitors of ASIC1a we found, but only potentiators for ASIC2a. Flat aromatic structure of the headgroup determines inhibition of ASIC1a while "V-shape" structure of the hydrophobic moiety favors potentiation of ASIC2a. Moreover, for some series of monoamines there was a correlation between action on ASIC1a and ASIC2a, the weaker ASIC1a inhibition, the stronger ASIC2a potentiation. Decay of response was accelerated by ASIC1a inhibitors as well as by potentiators. All compounds potentiating ASIC2a slowed down desensitization. Our results suggest that hydrophobic amines cause complex action on ASICs.
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St. Petersburg 194223, Russian Federation.
Elina I
EI
Nagaeva
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St. Petersburg 194223, Russian Federation.
Natalia N
NN
Potapieva
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St. Petersburg 194223, Russian Federation.
Maxim V
MV
Nikolaev
Institute of Experimental Medicine RAMS, 12 Akademika Pavlova str., St. Petersburg 197376, Russian Federation.
Valery E
VE
Gmiro
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St. Petersburg 194223, Russian Federation; St. Petersburg State University, Universitetskayanab., 7-9, St. Petersburg 199034, Russian Federation.
Lev G
LG
Magazanik
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 44 Thorez pr., St. Petersburg 194223, Russian Federation. Electronic address: denistikhonov2002@yahoo.com.
Denis B
DB
Tikhonov
D062565:Acid Sensing Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D000588:Amines; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D013329:Structure-Activity Relationship
D062565:Acid Sensing Ion Channels; D000588:Amines; D003510:Cyclohexanes; C506365:Cyclohexane
ASICs; Monoamines; Patch-clamp; Pharmacology; Structure-activity relationships