Identification of a pharmacophore of SKCa channel blockers.
Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and the periphery. Three subtypes of SK channels have so far been identified in different parts of the brain. Activation of the SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, reducing cell excitability. Blocking the SK channels might be beneficial in the treatment of depression, Parkinson's disease and cognitive disorders. However, few blockers of SK channels have been characterized. In this study, a pharmacophoric model of SK channels blockers is presented. It is based on a series of nonpeptidic compounds and apamin, a peptidic blocker. To create the pharmacophore model, the conformational space of nonpeptidic blockers was investigated to generate a series of distance constraints applied to a simulated annealing study of apamin. The resulting conformation was superimposed with the nonpeptidic blockers to give a pharmacophore.
Dilly
Sebastien
S
Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie Thérapeutique, EA1 043, 3 rue du professeur Laguesse, BP 83, 59006 Lille Cedex, France.
Graulich
Amaury
A
Farce
Amaury
A
Seutin
Vincent
V
Liegeois
Jean-Francois
JF
Chavatte
Philippe
P
D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000737:chemistry* / Q000494:pharmacology; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D001516:Bees; D002103:Cadaverine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D001381:Azepines; C508695:BQ1 compound; C508696:BQ2 cadaverine; C508697:BQ3 compound; D047028:Macrocyclic Compounds; D026902:Potassium Channel Blockers; D011804:Quinolines; D011806:Quinolinium Compounds; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D002103:Cadaverine