Compounds Structurally Related to Tamoxifen as Openers of Large-Conductance Calcium-Activated K+ Channel

Abstract

We found that a variety of compounds containing partial structures of tamoxifen showed activity as chemical modulators of large-conductance calcium-activated K ؉ channels (BK channels).Key words large-conductance calcium-activated K ϩ channel; tamoxifen; channel opener; (xeno)estrogen; electrophysiology Large-conductance calcium-activated K ϩ channels (BK channels) characteristically respond to two distinct physiological stimuli, i.e., changes in membrane voltage and in cytosolic Ca 2ϩ concentration.1) The BK channel opens in response to an increase in cytosolic Ca 2ϩ concentration and membrane depolarization, resulting in an increase of K ϩ efflux, which leads to rapid hyperpolarization of the excitatory membrane and thus reduces Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels. The BK channel is formed by a tetramer of the pore-forming a-subunit and up to four b-subunits that function to modulate the BK channel.2,3) Recent cloning studies also revealed the presence of multiple splice variants of a-subunits [4][5][6] and multiple subtypes of b-subunits (b 1 , b 2 /b 3 and b 4 ). 7-9) Thus, there is a large diversity of BK channels, which may be specific to tissues and organs. [4][5][6] Except for cardiac myocytes, the BK channels are expressed in a number of organ systems, such as smooth muscle cells, skeletal muscle cells, neuronal cells, and secretary epithelial cells, 10) and they have important physiological roles in modulating muscle contraction and neuronal activities, such as synaptic transmission. 11)These features and the widespread distribution of the channel throughout the central nervous system and in peripheral tissues offer rich opportunities for discovering novel therapeutic agents based on BK channel modulators, particularly openers.12,13) Chemical channel openers are expected to quench excitatory events that pathologically elevate the cytosolic Ca 2ϩ and induce depolarization of the cell membranes, and potentially have specificity for tissues and organs of interest. Well-characterized BK channel openers could be used to treat acute stroke, epilepsy, and bladder overactivity.14) There is some evidence for the utility of BK channel openers in the treatment of asthma, hypertension, gastric hypermotility and psychoses. 1) Recent studies have shown that the BK channel is one of the targets for the non-genomic effects of (xeno)estrogens, such as tamoxifen and estradiol. [15][16][17][18][19] The stimulatory action of tamoxifen and 17b-estradiol on the BK channel activity requires the presence of the b 1 subunit. [15][16][17][18][19] Herein, we show that compounds containing partial structures of tamoxifen can activate the human BK channels, possibly through action on the b 1 subunit.Compounds 3a-o were synthesized by means of McMurry condensation reaction of a substituted benzophenone derivative and 3-pentanone in the presence of TiCl 4 and zinc powder in dry THF with heating at reflux for 4-20 h. 20) Preliminary assay by using the fluorescent dye method with DiBAC 4 (3) was applied with rat rSlo...

Discovery of a Tamoxifen-Related Compound that Suppresses Glial l-Glutamate Transport Activity without Interaction with Estrogen Receptors

“…We synthesized several Tam-inspired compounds bearing identical substituents on one carbon atom of the olefin, 12 and found that two of them were potent inhibitors of astrocyte L-Glu transporters. The diethyl-substituted derivative 1 inhibited L-Glu transporters in the picomolar range (62.7 ± 7.48% of control at 1 pM; Figure 2A).…”

“…This structural complexity makes the stereospecific synthesis of Tam-related derivatives difficult. We thus focused on Tam-inspired compounds bearing identical substituents on at least one of the olefinic carbon atoms . It is well-known that the N , N -dimethylaminoethyl substituent on the phenolic oxygen atom and the regiochemistry of the tetrasubstituted olefin of Tam are crucial for ER binding activity .…”

“…We thus focused on Tam-inspired compounds bearing identical substituents on at least one of the olefinic carbon atoms. 12 It is well-known that the N,N-dimethylaminoethyl substituent on the phenolic oxygen atom and the regiochemistry of the tetrasubstituted olefin of Tam are crucial for ER binding activity. 13 So, we considered that more symmetrical derivatives of Tam might show reduced ER-binding ability.…”

Potassium Channel Openers: The Case of BK Channel Activators

“…In fact, besides their ample structural and chemical diversity, even exact comparisons between analogues described in different studies cannot be simply made, particularly because of the diversity of indications for which they are claimed as well as the plethora of the techniques and pharmacological models by which they are tested. The wide variety of different natural compounds [98], such as flavonoids and synthetic analogues [99,100], pimarane diterpenes and synthetic analogues [101][102][103], and other synthetic drugs, including tamoxifen and analogues [104] [105], anti-inflammatory fenamates [106] (Fig. (6)), chlorzoxazone [107] (Fig.…”