3,7-Diazabicyclane: a new narcotic analgesic.

The synthesis of a series of 9-phenyl-3,7-diazabicyclanes and 9-(m-hydroxyphenyl)-3,7-diazabicyclanes is described. Members of both series were tested for antinociception in rat tail withdrawal and mouse acetic acid writhing assays. Their affinities for opiate receptors in rat brain homogenate were also determined. The 9-phenyl compounds, 1a-c, were inactive. However, the 9-(m-hydroxyphenyl) analogues, 2a-c, were found to possess significant activity in the writhing assay, comparable to that of morphine. All activity was reversed by naloxone.

Alteration of in vivo and in vitro effects of heroin by esterase inhibition.

Selective inhibition of peripheral esterases by tri-ortho-tolyl phosphate in the mouse resulted in an increase in the analgetic activity of heroin, without affecting the activity of morphine. In vitro inhibition of esterases by paraoxon reduced the affinity of heroin for the opiate receptor, while that of morphine was unaffected. These results suggest that both central and peripheral esterases are involved in the metabolism of heroin and that interference with critical esterases can alter its pharmacologic and toxicologic effects.

2.8-A Structure of penicillin-sensitive D-alanyl carboxypeptidase-transpeptidase from Streptomyces R61 and complexes with beta-lactams.

The crystallographic structure of the penicillin-sensitive D-alanyl carboxypeptidase-transpeptidase from Streptomyces R61 has been solved to 2.8-A resolution. The 38,000-dalton serine peptidase has two regions of secondary structure, an alpha/beta cluster, and a region which contains five helical segments. The beta sheet is composed of five beta strands. The tertiary structure has no homology with the classic serine proteases or with the zinc carboxypeptidases. The binding at a common site of three types of beta-lactam (a penicillin, a cephalosporin, a monocyclic beta-lactam) and a desazacyclobutanone has been observed in Fourier difference maps. The binding site sequence is Val-Gly-Ser-Val-Thr-Lys. The beta-lactam ring lies near the enzyme's catalytic serine at position 37, and the C3 substituent of a cephalosporin falls near lysine 40.

Resolution, absolute configuration, and antiarrhythmic properties of the enantiomers of disopyramide, 4-(diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide.

Disopyramide was resolved by fractional crystallization of its diastereomeric bitartrate salts from methanol-acetone. Diastereomeric sulfonamides prepared from (+)-camphor-10-sulfonyl chloride and the primary amines obtained by LiAlH4 reduction of the resolved bases were separable by high-performance LC and were used to show that within experimental error resolution of disopyramide was complete. The absolute configuration was determined by X-ray crystallography. (+)-[(2R)-(-)-4-(Diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide (+)-(2R,3R)-bitartrate] crystallizes in space group P212121: a = 14.789 (4), b = 18.151 (4), c = 9.878 (2) A; Z = 4: Dx = 1.225, Dm (flotation C6H6/CCl4) = 1.226 g cm-3. The structure was solved by direct methods. The enantiomeric bitartrates were tested for antiarrhythmic properties. The enantiomeric bitartrate salts were equally effective in prolonging the effective refractory period (ERP) of rabbit ventricle. At 3 x 10(-6) M, the (-)-bitartrate [from (2S)-(+)-disopyramide] increased the ERP 21.8 +/- 6.3 ms and the (+)-bitartrate [from (2R)-(-)-disopyramide] increased the ERP 25.8 +/- 3.6 ms. At 1.5 x 10(-5) M no significant difference was noted, as the increases in the ERP were 41.2 +/- 8.9 and 50.5 +/- 6.3 ms for the (-)- and %+)-bitartrate, respectively.

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.

Synthesis and biological activity of cocaine analogs I: N-alkylated norcocaine derivatives.

N-Allylnorcocaine, N-dimethylallylnorcocaine, and N-cyclopropylmethylnorcocaine were prepared and examined for cocaine-like activity. The compounds were prepared by alkylation of norcocaine, which was obtained by demethylation of cocaine with 2,2,2-trichloroethyl chloroformate followed by zinc--acetic acid reduction. The compounds were evaluated by comparison with cocaine in causing disruption of milk intake in rats, behavioral modification in squirrel monkeys, and inhibition of 3H-serotonin uptake by rat synaptosomes. The compounds showed cocaine-like activity less potent than cocaine in the latter two tests and were inactive in the milk intake test.