Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.

Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).

Synthesis and antibacterial activity of some novel 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. Potent antistaphylococcal agents.

The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylates has provided access to the corresponding 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacterial activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms does not seem to be important for good Gram positive activity. For 1-cyclopropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-fluoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity against Staphylococcus aureus ATCC 29213. There is also a correlation between the substitution on the 7-(4-pyridinyl) group and the Gram positive activity, particularly for S. aureus, clearly indicating that the 2,6-dimethylpyridinyl group is optimal. The MIC50 value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 microgram/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 microgram/mL, respectively, against this organism.

4,5-Dihydro-1-phenyl-1H-2,4-benzodiazepines: novel antiarrhythmic agents.

A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 microM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for ventricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.

Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8- difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarb oxylic acid and related derivatives.

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.