Centrally acting emetics. 10. Rigid dopamine congeners derived from octahydrobenzo[f]quinoline.

In a study of conformational requirements for certain dopaminergic agonist molecules, a series of conformationally predictable dopamine congeners related to cis- and trans-octahydrobenzo[f]quinoline was prepared. The complexity and equivocal character of the reduction of variously substituted 4-methyl-1,2,3,4,5,6-hexahydrobenzo[f]quinolines were demonstrated and studied. It was shown that several literature methods for reduction of these systems were in error regarding the stereochemical nature of the product(s). It has been concluded that geometrically specific and predictable reductions of these hexahydrobenzo[f]quinolines seem unlikely to attain, and a plausible rationalization for this conclusion has been proposed. Pharmacologic data on the compounds prepared are consistent with our earlier proposals of a biologically significant conformation of dopamine for emesis, the pecking syndrome in pigeons, and other physiological effects.

Ames test of 1-(X-phenyl)-3,3-dialkyltriazenes. A quantitative structure-activity study.

The mutagenicity of 1-(X-phenyl)-3,3-dialkyltriazenes was tested in the Ames test using Salmonella typhimurium TA92. The following quantitative structure-activity relationship (QSAR) was formulated: log 1/C = 1.09 log P -1.63 sigma+ + 5.58. In this expression, C is the molar concentration of triazene producing 30 mutations/10(8) bacteria above background. This equation is based on 17 congeners and has a correlation coefficient of 0.974. The QSAR for mutagenicity is compared with QSAR for antileukemia action and toxicity (LD50) in mice. The mutagenicity of aflatoxin B (log 1/C = 9.5) and DTIC (log 1/C = 3.0) have also been determined.

Antitumor 1-(X-aryl)-3,3-dialkyltriazenes. 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure-activity relationships of 1-(X-phenyl)-3,3-dialkyltriazenes in mice.

A series of 11 triazenes (X-C6H4N=NNRCH3) was characterized for toxicity in mice (LD50). The quantitative structure-activity relationship (QSAR) obtained for toxicity was compared with the QSAR for antitumor activity. The close correspondence of the two QSAR leaves essentially no means for the synthesis of more potent, less toxic triazenes.

Antitumor 1-(X-aryl)-3,3-dialkyltriazenes. 1. Quantitative structure-activity relationships vs. L1210 leukemia in mice.

Quantitative structure-activity relationships (QSAR) have been formulated for phenyl-, pyrazolyl-, and imidazolyltriazenes acting L1210 leukemia in mice. All three sets of congeners have the same ideal lipophilicity (log Po approximately 1). Electron releasing substituents increase potency; ortho substitution decreases activity. The synthesis of a number of new triazenes and some of their partition coefficients are reported.

Inhibition of the sympathetic nervous system by a series of heterocyclic congeners of dopamine.

A series of heterocyclic congeners of dopamine (GJH-series) with different positions of phenolic oxygens and with the possibility of cis and trans isomerism at the 4a-10b ring juncture was evaluated in vitro and in vivo for dopaminergic activity. Two compounds, GJH-166 and GJH-171, were found to suppress the positive chronotropic response induced by stimulation of the right cardioaccelerator nerves. These effects were antagonized by haloperidol. GJH-166, in doses as low as 9.5 x 10(-4) mugmol/kg reduced the resting heart rate in cats anesthetized with alpha-chloralose. GJH-166 and GJH-171 antagonized pressor responses induced by bilateral carotid occlusion and stimulation of the central stump of the sciatic nerve. The results outlined in this manuscript support the hypothesis that the extended conformation of the dihydroxyhenylethylamine moiety of dopamine with a trans isomeric form is favorable for dopaminergic agonist activity.

Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.