Search

A chemosyndrome of para- depsides based on methyl 4-O-demethylbarbatate (3) has been detected in Erioderma lichens and the structures of the metabolites have been established by unambiguous syntheses. New depsides include methyl 5-chloro-4-O-demethylbarbatate (4), methyl eriodermate (5), methyl 2'-0-methyleriodermate (6), methyl 2-O-methyleriodermate (7), methyl 4-O-methyleriodermate (8) and methyl 2,2'-di-O-methyleriodermate (9).

The depsidones norpannarin (4) and norargopsin (5) have been prepared by unambiguous synthesis and shown to co-occur with nordechloropannarin (7), pannarin (3) and argopsin (2) in Erioderma chilense.

Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [³H]-8-OH-DPAT from rat brain 5-HT1A receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c−e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (7l) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT1A receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT1A receptor affinity. The racemic mixtures of the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high enantiomeric 5-HT1A receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT1A receptor agonist, stimulating both autoreceptors and postsynaptic receptors.

The amino terminus of mouse epidermal growth factor (mEGF) was coupled directly to the aldehyde end of dextran through a reductive amination procedure. The highest coupling efficiency was ~80% and could be reached after ~24 h of reaction time at pH 8. Gel filtration on Sephadex G-50 Fine removed free mEGF from the conjugate. Preparative polyacrylamide gel electrophoresis was used to separate the conjugate from excess noncharged dextran. The conjugate bound specifically to the EGF receptor on cultured glioma cells as shown in displacement tests with free mEGF. The conjugate was stable in the pH interval 4−9, in 2 M sodium chloride, in 7 M urea, and in human serum and could still bind to the EGF receptor after such treatments. The conjugates are candidates for targeted nuclide therapy.

Although many different types of compounds have been tested for 5-hydroxytryptamine1A (5-HT1A) binding affinity, much remains to be learned about the structural requirements associated with 5-HT1A agonism, partial agonism, and antagonism. The present study uses the forskolin-stimulated adenylate cyclase (FSC) assay as a functional screen in rat hippocampal membranes to examine structure-activity relationships for a series of enantiomers of novel analogs of the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The findings illustrate that there can be large enantiomeric differences in intrinsic activity at the 5-HT1A receptor, independent of enantiomeric effects on binding affinity. Generally, for each enantiomeric pair exhibiting stereoselective 5-HT1A binding, the enantiomer with the higher affinity also displayed the greater amount of 5-HT1A intrinsic activity in the FSC assay. Interestingly, the enantiomers of 8-OH-DPAT itself displayed stereoselective differences in intrinsic activity but not 5-HT1A affinity. Several of the compounds, namely (S)-UH-301, (2R,3R)-CM-12, and (1S,2R)-LEA-146, may have potential as prototypes for selective 5-HT1A antagonists, and (S)-UH-301 itself may be useful as a selective 5-HT1A antagonist. The FSC data presented here are in good agreement with reported measures of in vivo 5-HT1A activity, which were in part the basis of a recently proposed model for the 5-HT1A pharmacophore [J. Med. Chem. 34: 497-510 (1991)].