Different Modes of Blockade by p-Phenylene-polymethylene Bis-ammonium Compounds of the Nicotinic Acetylcholine Receptor Channel in Skeletal Muscle Cells of Mice

The structure-activity relationships of five newly synthesized p-phenylene-polymethylene bis-ammonium (PMBA: C6H4[(CH2)nN+R3]2) compounds were investigated on the blockade of the nicotinic acetylcholine receptor (nAChR) channel. The cell-attached patch clamp configuration was used to measure single-channel currents in the endplate region of single flexor digitorum brevis muscle cells of adult mice. The bis-trimethylammonium compounds PMBA-1 (n = 4, R = CH3) and PMBA-23 (n = 6, R = CH3) produced channel opening above 0.3 microM and open channel blockade above 10 and 3 microM, respectively. The bis-triethylammonium compounds PMBA-43 (n = 1, R = CH2CH3) and PMBA-24 (n = 6, R = CH2CH3) showed no channel opening action, but PMBA-21 (n = 4, R = CH2CH3) opened channels weakly at 3 and 10 microM. These bis-triethylammonium compounds exerted different blocking actions on acetylcholine-activated channel currents. Above 10 microM PMBA-43, like tetraethylammonium, blocked open channels by decreasing the mean open time by rapid partial closing of the channel during the open-phase. At 10 microM, PMBA-21 blocked open and closed channels by decreasing the opening frequency by means of an irregular sequence of short pulses. At 0.3 microM, PMBA-24 blocked closed or nonconducting channels by decreasing the opening frequency without producing changes in mean open time. These results indicate that by lengthening the distance between two nitrogen atoms in the bis-triethylammonium group of PMBA, open channel blockade changes to closed channel blockade.(ABSTRACT TRUNCATED AT 250 WORDS)