Bis-quaternary ammonium salts and methods for modulating neuronal nicotinic acetylcholine receptors

A bis-quaternary ammonium compound of Formula (I)

• X2⊖⊕R2—R—R1⊕⊖X1 (I)
• wherein X1⊖ and X2⊖ are each independently an organic or inorganic anion;
• wherein R is selected from the group consisting of —(CH2)12—;
• wherein R1 and R2 are each six membered rings as shown in formula (IIA), wherein each ring of R1 and R2 has one quaternized nitrogen atom, and the ring atoms from R1 and R2 which are attached to R cannot both be nitrogen atoms:
• wherein one of A1, A3, and A4, is nitrogen and the remaining A1, A2, A3, A4, A5, and A6 are carbon;
• wherein R5, R7, R9, R11, and R13 are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, halo, cyano, nitro, SOY1, SO2Y1, SO2OY1 or SO2NHY1, where Y1 is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y1 is not hydrogen in SOY1 and if Y1 is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• COY2, where Y2 is selected from hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, arylalkynyl, or heterocyclic, and where if Y2 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group;
• OY3, where Y3 is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, arylalkynyl, acyl, alkylsulfonyl, or heterocyclic, where if Y3 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen;
• NY4Y5, where Y4 and Y5 are each independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, or heterocyclic, where if Y4 or Y5 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen;
• SY6, where Y6 is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, arylalkynyl, or heterocyclic, and where if Y6 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur;
• and any of R5, R7, R9, R11, or R13 attached to the quaternized nitrogen is independently a straight or branched alkyl group of four carbons or fewer.