The conformation of the A-ring fragment of neuromuscular blocking agents structurally related to pancuronium. X-Ray structure determinations, molecular mechanics calculations and molecular dynamics simulations

Abstract

Org 9616 [1-{(2β,3α,5α,16β,17α)-3-acetoxy-17-(1-oxobutoxy)-2-(piperidin-1-yl)androstan-16-yl}-1-methylpiperidinium bromide] is a non-depolarizing neuromuscular blocking agent, structurally related to pancuroniam. The reported crystal structures of the free base and the HBr salt show that the monoquaternary aminosteroid changes from a vecuronium-like conformation with the A-ring substituents in an axial orientation to a pancuroniam-like conformation with the A-ring substituents in an equatorial orientation upon protonation. The conformations observed in the X-ray structures of Org. 9616 and several other neuromuscular blockers, suggest a different conformational behaviour of the piperidino group attached to the A-ring of the steroid skeleton in pancuroniam and protonated veuronium. The conformational flexibilities of the A-ring and substituents in pancuroniam, vecuronium and protonated veuronium are more closely investigated by means of molecular mechanics calculations and molecular dynamics simulations. A model explaining the difference in selectivity between pancuroniam and vecuronium is based on the conformational behaviour of this part of the molecule. The relevance of the presented model for the 3β-methyl analogues of pancuroniam and vecuronium and the 2β-trimethylammonium analogue of pancuroniam is discussed.