Stereochemistry of a Curare Alkaloid: O,O′,N -Trimethyl- d -Tubocurarine

Abstract

The three-dimensional structure of 0,0',-N-trimethyl-d-tubocurarine, a neuromuscular blocking agent, has been determined by x-ray crystallography. This may help to provide insight into its pharmacologic action.d-Tubocurarine is a curare alkaloid that has been used for centuries by South American Indians to prepare poison arrows for hunting wild animals for food. Death results from respiratory paralysis and subsequent asphyxiation. Its major action is the interruption of transmission of a nerve impulse at the neuromuscular junction. This is thought to reflect complex formation between the drug and cholinergic receptors located at the postjunctional membrane, competitively blocking the transmitter action of acetylcholine (1). The bis-quaternary ammonium structure of d-tubocurarine and its more potent derivative, O,O',N-trimethyl-dtubocurarine (see Fig. 1), suggests that coulombic interaction occurs between the cationic centers of the drug and certain anionic groups of the receptor site, and that these, as well as stereo-specific van der Waals interactions, probably account for its binding specificity and biological activity.We report here the crystal and molecular structure of 0,0',-

The crystal structure, absolute configuration and stereochemistry of (+)-tubocurarine dibromide methanol solvate: a potent neuromuscular blocking agent

“…The methyl group on the N atom of the tertiary tetra-hydroisoquinoline ring is axial in the dibromide but equatorial in the dichloride. The conformation of the methylated derivative O,O',N-trimethyl-(+)-tubocurarine diiodide (Sobell et al, 1972) is similar to (+)-tubocurarine dibromide, indicating that methylation of the two free hydroxyl groups [0(39) and 0(42)] and the quaternization of N(1) has no major effect on the relative orientation of their respective rings. As noted by Sobell et al (1972) the tubocurarine molecule has two major faces: one is largely hydropbilic (the upper, in Fig.…”

Curariform Antagonists Bind in Different Orientations to the Nicotinic Receptor Ligand Binding Domain

“…Members of the curare family contain two positively charged nitrogen atoms spaced 9 -11 Å apart (11,12), and these have been shown to span the interface between ␣ and non-␣ subunits (20). Many structurally unrelated competitive antagonists of the end plate AChR also contain two positively charged nitrogens, with the correct spacing, and like curare are thought to span the subunit interface.…”

“…Curare binds more tightly to the ␣Ϫ⑀ than to the ␣Ϫ␦ site, and thus its functional antagonism at tens of nanomolar concentrations results from occupancy of this high affinity binding site. Curariform antagonists contain a rigid, cyclic hydrocarbon scaffold bearing two tetrahydroisoquinoline rings and two electron-deficient nitrogen atoms separated by about 9 Å (11,12). Thus two appropriately spaced, positively charged centers represent the minimal components required in a high affinity competitive antagonist, also known as the antagonist pharmacophore.…”

The actions of tubocurarine at the frog neuromuscular junction.

“…The simplest interpretation of ion channel blockage is to suppose that tubocurarine can be inserted into, and hence plug, the ion channel. Crystallographic studies (Sobell, Sakore, Tavale, Canepa, Pauling & Petcher, 1972;Codding & James, 1973;Reynolds & Palmer, 1976) show that the molecule has a substantial degree of flexibility, and that the six rings do not all lie in the same plane. It can adopt a curved conformation with a convex surface that is largely hydrophilic and a concave surface that is almost entirely hydrophobic.…”