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Triarylmethanes, a new class of cx50 inhibitors.

Bodendiek SB, Rubinos C, Trelles MP, Coleman N, Jenkins DP, Wulff H, Srinivas M - Front Pharmacol (2012)

Bottom Line: We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds.The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel.In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Davis, CA, USA.

ABSTRACT
The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC(50)s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K(+) and Na(+) channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.

No MeSH data available.


Related in: MedlinePlus

Chemical synthesis scheme. a, Grignard reaction; b, CH3COCl; c, Excess of amine; d, CuCN; e, NH3.
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Figure 3: Chemical synthesis scheme. a, Grignard reaction; b, CH3COCl; c, Excess of amine; d, CuCN; e, NH3.

Mentions: Clotrimazole (CAS No. 23593-75-1), triphenylmethane (CAS No. 519-73-3), triphenylmethyl chloride (CAS No. 76-83-5), triphenylmethanol (CAS No. 76-84-6), 3,3,3-triphenylpropionic acid (T51, CAS No. 900-91-4), (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (T52, CAS No. 22348-32-9), (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (T53, CAS No. 112068-01-6), diphenyl-4-pyridylmethane (T160, CAS No. 3678-72-6), and triphenylmethylamine (T162, CAS No. 5824-40-8) were purchased from Sigma-Aldrich (St. Louis, MO). Tetraphenylmethane (T161, CAS No. 630-76-2) was purchased from Alfa Aesar (Ward Hill, MA). 2-Chlorotrityl chloride (T3-Cl, CAS No. 42074-68-0) and diphenyl-4-pyridylmethanol (T50, CAS No. 1620-30-0) were purchased from TCI America (Portland, OR). T1-T4, T9, T11, T13, T20, T34, T35, T39, T41, T43, T44, T54, T57, T61, T64, T66-T75, T78-T80, T85, and T97 were available in the Wulff laboratory compound library and had been previously synthesized and characterized (Wulff et al., 2000). The remaining compounds were synthesized using Grignard, chlorination and alkylation reactions described as general methods A, B, and C (see also Figure 3). New chemical entities (NCEs) were characterized by melting point (Melting Point B-540, Büchi), 1H-NMR (Avance 500, Bruker), mass spectrometry (MS: LCQ, Thermo Scientific; HRMS: LTQ-Orbitrap XL Thermo Scientific), and/or combustion analysis (2400 Series II combustion analyzer, Perkin Elmer). All MS and HRMS spectra were recorded with ESI as ionization mode if not stated otherwise. In cases where no sufficient analytical data for previously reported compounds (T109, T117, T129, T141, T143, T144, T154-OH, and T165) were available 1H-NMR, MS and/or combustion data in addition to melting points are also provided.


Triarylmethanes, a new class of cx50 inhibitors.

Bodendiek SB, Rubinos C, Trelles MP, Coleman N, Jenkins DP, Wulff H, Srinivas M - Front Pharmacol (2012)

Chemical synthesis scheme. a, Grignard reaction; b, CH3COCl; c, Excess of amine; d, CuCN; e, NH3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368247&req=5

Figure 3: Chemical synthesis scheme. a, Grignard reaction; b, CH3COCl; c, Excess of amine; d, CuCN; e, NH3.
Mentions: Clotrimazole (CAS No. 23593-75-1), triphenylmethane (CAS No. 519-73-3), triphenylmethyl chloride (CAS No. 76-83-5), triphenylmethanol (CAS No. 76-84-6), 3,3,3-triphenylpropionic acid (T51, CAS No. 900-91-4), (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (T52, CAS No. 22348-32-9), (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (T53, CAS No. 112068-01-6), diphenyl-4-pyridylmethane (T160, CAS No. 3678-72-6), and triphenylmethylamine (T162, CAS No. 5824-40-8) were purchased from Sigma-Aldrich (St. Louis, MO). Tetraphenylmethane (T161, CAS No. 630-76-2) was purchased from Alfa Aesar (Ward Hill, MA). 2-Chlorotrityl chloride (T3-Cl, CAS No. 42074-68-0) and diphenyl-4-pyridylmethanol (T50, CAS No. 1620-30-0) were purchased from TCI America (Portland, OR). T1-T4, T9, T11, T13, T20, T34, T35, T39, T41, T43, T44, T54, T57, T61, T64, T66-T75, T78-T80, T85, and T97 were available in the Wulff laboratory compound library and had been previously synthesized and characterized (Wulff et al., 2000). The remaining compounds were synthesized using Grignard, chlorination and alkylation reactions described as general methods A, B, and C (see also Figure 3). New chemical entities (NCEs) were characterized by melting point (Melting Point B-540, Büchi), 1H-NMR (Avance 500, Bruker), mass spectrometry (MS: LCQ, Thermo Scientific; HRMS: LTQ-Orbitrap XL Thermo Scientific), and/or combustion analysis (2400 Series II combustion analyzer, Perkin Elmer). All MS and HRMS spectra were recorded with ESI as ionization mode if not stated otherwise. In cases where no sufficient analytical data for previously reported compounds (T109, T117, T129, T141, T143, T144, T154-OH, and T165) were available 1H-NMR, MS and/or combustion data in addition to melting points are also provided.

Bottom Line: We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds.The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel.In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Davis, CA, USA.

ABSTRACT
The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC(50)s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K(+) and Na(+) channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.

No MeSH data available.


Related in: MedlinePlus