Structure-activity studies leading to potent chloride channel blockers:...

5e-tert-Butyl-2e-[4-(substituted-ethynyl)phenyl]-1,3-dithianes+ ++ with selected functional groups (R) on the ethynyl moiety are potent blockers of the GABA-gated chloride channel measured as inhibitor concentration (IC50) for 4-n-[3H]propyl-1-(4-ethynylphenyl)-2,6,7- trioxabicyclo[2.2.2]octane binding to bovine brain membranes. The terminal R substituents were introduced by coupling 5e-tert-butyl-2e-(4-iodophenyl)-1,3-dithiane with HC identical to CR or 5e-tert-butyl-2e(4-ethynylphenyl)-1,3-dithiane with XR. The potency of the parent compound (R = H) with an IC50 of 21 nM is equaled or exceeded by up to 7-fold (i.e. IC50 = 3-21 nM) by several carboxylic acids [R = (CH2)nCO2H (n = 0-3), (CH2)nOCH2CO2H (n = 1-3), and CH2SCH2CO2H] and their esters and two phosphonic acids (CH2CH2PO3H2 and CH2OCH2PO3H2) but not their esters. These carboxylic and phosphonic acids (and their salts) include the most potent water-soluble chloride channel blockers known. Conversion to the monosulfones increases the activity of the R = H and CH2OH analogs by 1.2- to 3-fold but decreases that of the R = CH2CH2CO2R' (R' = H or CH3) derivatives by 3- to 13-fold. Quantitative structure-activity analyses for 44 2-[4-(substituted-ethynyl)phenyl]-dithianes suggests that the principal feature of the R substituent for high activity is its polarizable volume modeled as molecular refractivity, i.e. this substituent is not a well-defined pharmacophore and undergoes a structurally non-specific interaction with the receptor. These observations lay the background for preparing candidate affinity probes.