Structure investigations of agonists of the natural neurotransmitter acetylcholine, IV. X-ray structure analyses of trimethylpentylammonium-chloride and (4-acetoxybutyl)trimethylammonium-iodide.

The crystal structures of the title compounds which display cholinergic activity at the ganglionic receptor have been determined by X-ray structure analysis. [(CH3)3N+C5H11]Cl- (1) crystallizes in the orthorhombic space group Pbnm with half a formula unit per asymmetric unit, a = 11.381(14), b = 12.871(17), c = 7.316(4) A. The intensities of 1106 independent reflections were collected with an automatic diffractometer. The structure refinement converged at R = 0.133 for the 355 observed reflections. The cation of 1 is disordered. [(CH3)3N+ (CH2)4-O-C(O)-CH3]I- (2) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with four formula units per unit cell, a = 16.783(8), b = 10.276(6), c = 7.427(10) A. The intensities of 1469 independent reflections were collected. The structure refinement converged at R = 0.071 for 1383 observed reflections. In both compounds the trimethylammonio methyl groups are coordinated nearly tetrahedrally by four anions in the first coordination sphere. Anions which occupy a special face type (B) of the tetrahedron of the (CH3)3N+ -CH2-group may be treated as a "model binding site" of the receptor. In the crystal structure of 2 the anions occupying B-type faces form together with the ammonium nitrogen and the carbonyl oxygen so called "Activity triangles". The almost equal geometries of these activity triangles are correlated with the mode of pharmacological action.

Structure investigations of agonists of the natural neurotransmitter acetylcholine, V. Structure-activity correlations for cholinergic stimulants derived from crystal structures of their halides.

General features of crystal structures of halide salts of cholinergic stimulants can be interpreted in terms of substrate-receptor interactions. The monoatomic counterions in the crystal structures are discussed as models for the binding site of the receptor with respect to the ammonium group of the cholinergic neurotransmitters. In the crystal structures the anions occupy the tetrahedral faces of the quaternary trimethylammonio methyl or related groups in a specific geometry. Crystallographic and pharmacological evidence indicates that these groups should preferentially interact with the receptor via a specific face type (B-type face). The directionality of the interaction is derived from the vectors joining N+ with the anions occupying B-type faces. So called "activity triangles", formed by the nitrogen of the ammonium group, a second polar centre of the neurotransmitter cation and a counterion occupying a B-face of the ammonium group, provide a structural criterion for the differentiation between muscarinic and nicotinic activity. It is shown that structure-activity relationships of cholinergic stimulants do not depend on the conformational details of the neurotransmitter cations, but primarily on the relative positions of the polar centres of the cations with respect to the anionic binding site of the receptor.

Structure investigations of agonists of the natural neurotransmitter acetylcholine. VI. X-ray structure analysis of trimethyl[2-(propionyloxy)ethyl]-ammonium-iodide (O-propionylcholine-iodide).

The title compound crystallizes in the orthorhombic, noncentrosymmetric space group Pna2(1) with a = 10.241(11), b = 12.903(12), c = 9.312(9) A and with one formula unit per asymmetric unit. The stereochemically comparable torsion angles of the cation of 1 and of acetylcholine chloride are analogous. In the crystal structure the trimethylammonio methyl group is surrounded by three anions in the first coordination sphere. The geometry of a triangle formed by one of these counterions which occupies a special face of the N+C4 tetrahedron of the (CH3)3N+-CH2-R moiety, the nitrogen atom of the ammonium group and the oxygen atom of the carbonyl group is typical for nicotinic agonists.

Structure investigations of agonists of the natural neurotransmitter acetylcholine, III. X-ray structure analysis of (2-ethoxyethyl)trimethylammonium chloride.

To elucidate the structure-activity correlations we have performed an X-ray structure analysis of the title compound (1), which is a muscarinic agonist of the natural neurotransmitter acetylcholine. 1 crystallizes in the monoclinic space group P2(1)/n with 2 molecules per asymmetric unit. Lattice parameters are: a = 10.375(6), b = 12.468(5), c = 15.274(17) A; beta = 95.32(7) degrees. The structure was solved by direct methods and refined to an R-value of 0.14 for 1828 observed reflections. Both cations in the asymmetric unit are disordered. In the crystal structure at least four conformations of the cation occur, indicating a pronounced conformational flexibility of the neurotransmitter cation. The anions are arranged stereospecifically with respect to the quaternary trimethylammonio methyl group. The geometry of triangles which are defined by a nitrogen of the quaternary ammonium group and an ether oxygen on one hand and an anion occupying a specific type of tetrahedral faces of a (CH3)3N+ CH2 group on the other hand, is characteristic for muscarinic agonists if they contain an ether or ester oxygen in the analogous position to the ester oxygen of acetylcholine.

Structure investigations of agonists of the natural neurotransmitter acetylcholine II [1]. X-ray structure analysis of trimethyl(4-oxopentyl)ammonium-chloride.

The crystal structure of Trimethyl(4-oxopentyl)ammonium-chloride ([(CH3)3N--(CH2)3COCH3]Cl-) (1) was determined by an X-ray structure analysis. 1 crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 10.440 (3), b = 14.600 (9), c = 6.804 (9) A and with four formula units per unit cell. The structure was solved by a Patterson and a successive Fourier synthesis. The least squares refinement yielded an R-value of 0.064 for 1077 observed reflections. The cation of 1 is derived from acetylcholine by replacement of the ester oxygen with a CH2 group. It shows a potent nicotinic activity and a significant difference in conformation as compared with acetylcholine. In the crystal structure the anions are oriented stereospecifically with respect to the tetrahedron of the quaternary ammonium group. The geometry of two triangles formed by the quaternary nitrogen atom, the oxygen atom of the carbonyl group, and by either of the two anions nearest to the quaternary ammonium group is characteristic for the nicotinic activity of 1.

Some aspects concerning conformation of polypeptide chains in proteins.

The structure of (S)-N,N'-di-tert-butyl-2-[N-(1-phenylethyl)benzamido] malonamide contains two fragments of a polypeptide chain. This compound therefore can be taken as a model substance for details of protein conformation. In the crystalline state one peptide chain of the model molecule incorporates a hydrogen bond between two adjacent nitrogen atoms in the backbone. The acceptor for the hydrogen is the pz-orbital at the proton accepting nitrogen. The occurence of such hydrogen bonds in proteins might explain some correlations found between phi and psi torsion angles. In addition a correlation between torsion angle /psi/ and the bond angle tau at C alpha in the backbone of polypeptide chains could be established. The model substance also contains a "frozen" back side attack of a C = O group on the tetrahydrally coordinated C alpha in analogy to the SN2 substitution reaction of the Walden inversion with a trigonal bipyramidal transition state.