Model studies of the function of blockers on the small conductance potassium ion channel.

A correlation between KI (equilibrium dissociation constants) and IC50 (concentration at 50% inhibition) inhibitors for the family of blockers of the small conductance potassium ion channels and their intrinsic characteristics like molecular mass and volume have been investigated. Most of the blockers in the family are not selective, in contrast to apamin - an 18 amino acid bee venom toxin - that is known to be a highly potent and selective blocker of these channels. Differences and similarities between the blockers have been analyzed, pointing toward the origin of their selectivity and relative potency. In conclusion, an ion channel blocking is a process controlled mainly by diffusion, in accordance with previous experimental results.

Structure-activity relationship of some new anti-arrhythmic phenytoin derivatives.

The pharmacological activity of nine anti-arrhythmic phenytoin derivatives was assessed in preventing chloroform-induced arrhythmia. The compounds were tested in vitro on isolated heart of the rat. Four compounds were chosen as representative of the spatial characteristics of the studied group, and X-ray structure analyses were carried out on them. Because the protonated form is present in physiological milieu, conformational analysis was performed on the protonated form of the four representatives and in addition on the compound showing the highest anti-arrhythmic activity. It was found that substitution of the imidazolidinone ring of phenytoin at position 3 by a chain containing a tertiary amine nitrogen atom changes the affinity profile from inactivated (phenytoin-like) to activated (quinidine-like) cardiac sodium channels. The activity of the studied compounds relies on the presence of protonated tertiary nitrogen atom, at least one phenyl ring, and flexibility of the molecule, which enables the spacer to assume a desired length.

Search for New Anticonvulsant Compounds, Part 2. Structure-activity relationship studies of new N-substituted amides of alpha-piperazine-gamma-hydroxybutyric acid as active anticonvulsants.

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of N-benzylamides of alpha-(4-benzylpiperazine)-gamma-hydroxybutyric acid (B), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100-300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B.

Spiranes 6. Ring A homologues of N-benzyloxy-2-azaspiro[4.4]nonane-1,3-dione. Synthesis, X-ray analysis and anticonvulsant evaluation.

A series of spirosuccinimides was synthesized and evaluated for anticonvulsant activity. The study was designed to determine the effect of varying the carbocyclic (ring A) nucleus, while maintaining the heterocyclic ring constant, on anticonvulsant activity. Results indicate that maximum activity was obtained with the ring A comprised of a six-membered spiro ring system, 2a, one methylene group greater than that previously reported for N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione, 1, the prototype analogue. Compound 2a was active in the MES test providing protection at 100 mg/kg, as was the spirododecane analog 2g. X-ray analysis revealed significant differences between active 2a, and the inactive spirooctane analogue, 2f. However these differences could not explain the unexpected activity demonstrated by the spirododecane analog 2g.

The structure-activity relationship of a new anti-arrhythmic agent 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one.

This paper reports the synthesis of the new compound 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one (Ac-MG-1). Preliminary pharmacological assessment revealed that Ac-MG-1 possesses anti-arrhythmic activity and a local anesthetic effect. The crystal structure of Ac-MG-1 was determined by X-ray diffraction, and conformational analysis was performed both for Ac-MG-1 and for other derivatives of (arylpiperazinyl)propylpyrrolidin-2-one.

Molecular and electronic structures of two (anticonvulsant) diphenylhydantoin derivatives.

1-Benzyl-5,5-diphenyl-2,4-dioxo-3-imidazolidineacetic acid (AC), M(r) = 400.434, triclinic, P1, a = 8.7640 (3), b = 11.112 (1), c = 11.323 (2) A, alpha = 102.10 (2), beta = 95.44 (5), gamma = 109.12 (1)., V = 1002.65 (30) A3, Z = 2, Dx = 1.33 g cm-3, F(000) = 420, mu(Mo K alpha) = 0.852 cm-1, T = 293 K, R = 0.066 for 5551 unique observed reflections. The compound crystallizes from ethanol at room temperature in the form of colourless prism. 3-(2,4-Dichlorobenzyl)-5,5-diphenyl-2,4-dioxo-1-imidazolidineacetic++ + acid (AD), M(r) = 469.323, monoclinic, P2(1), a = 8.0399 (7), b = 9.7237 (6), c = 26.9768 (12) A, beta = 94.281 (4)., V = 2102.92 (96) A3, Z = 4, Dx = 1.48 g cm-3, F(000) = 968, mu(Mo K alpha) = 3.417 cm-1, T = 293 K, R = 0.066 for 5677 unique observed reflections. The compound crystallizes from ethanol at room temperature in the form of colourless prisms. Two approaches are employed in trying to understand the known differences in pharmacological activity: an analysis of the molecular geometries, and electronic structure calculations. A detailed analysis is made of the molecular geometries both from the X-ray diffraction results, and following energy minimization with molecular mechanics. The ab initio calculations employ the energy-minimized conformations. Several electronic properties are intercompared for AC, AD and their common parent molecule diphenylhydantoin (DPH). The analyses of geometry and electronic structure indicate dissimilarities between active and inactive compounds which may be linked to differences in the activity.

Synthesis and CLOGP correlation of imidooxy anticonvulsants.

Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss structure activity and the Craig plot analytical approaches as well as a semiempirical method. CLOG P analysis was also applied to this series after experimentally determining the NOR fragment. All compounds were minimized and these physicochemical parameters correlated to anticonvulsant activity. Several interesting substituted benzyloxy compounds emerged from this study: the 2',4'-dichloro (2b), 4'-(trifluoromethyl) (2c), 2'-bromo (2d), 3'-chloro (2o), 2'-chloro (2r), 2'-fluoro (2p), and 3'-fluoro (2w) analogs, all of which had comparable, or better activity than the parent unsubstituted analog (2a). X-ray crystal analysis of the active 2a versus inactive N-benzyl-2-azaspiro[4.4]nonane-1,3-dione (10) is discussed.

Quinidine as a muscarinic antagonist: a structural approach.

The synthesis, spectroscopic characteristics, and single-crystal X-ray structural analysis of quitenidine methyl ester monohydrate, a derivative of the muscarinic antagonist quinidine, are presented. Quitenidine methyl ester monohydrate (C20H24N2O4.H2O) crystallizes in the orthorhombic space group P2(1)2(1)2(1), with a = 16.69(3) A, b = 12.46(2) A, c = 9.70(1) A, and Z = 4. The crystal structure was refined to a discrepancy factor (R) of 0.097. Substitution of the quinidine vinyl chain with a carboxymethyl group does not influence the conformation. The carboxymethyl group is positionally disordered, a fact that complicates refinement of the structure. The water molecule is bonded to the quinuclidine nitrogen atom, and the hydroxyl group forms an intermolecular hydrogen bond with the quinoline nitrogen atom. The molecular structure of the ester was compared with those of quinidine, quinine, and four other antimuscarinic agents. An approximately linear relationship between the distance from the nonaromatic nitrogen to the plane of the aromatic part of the molecules and the blocking potency of these agents was noted; the greater this distance, the more potent is the antagonist.

Structure of (R)-(-)-7-[2-(1-hydroxy-2-butylamino)ethyl]theophylline hydrochloride.

C13H22N5O3+.Cl-, Mr = 331.803, monoclinic, C2, a = 21.821 (3), b = 11.810 (2), c = 6.978 (2) A, beta = 100.7 (3) degrees, V = 1767.01 A3, Z = 4, Dm = 1.25, D chi = 1.23 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 2.051 mm-1, F(000) = 704, T = 293 K, R = 0.065 for 1512 unique observed reflections. The compound is a potential antiarrhythmic and the molecule has the typical synclinal conformation for the -NH-CH-CH2-OH fragment of the side chain [tau CC = 56.5 (8) degrees] exhibited by these compounds. The Cl anion is hydrogen bonded to the N atom of 2-aminobutanal: N...Cl = 3.075 (1) A; N-H...Cl = 169.6 (5) degrees.