The affinity, selectivity and biological activity of telenzepine enantiomers.

The binding of the enantiomers of telenzepine to muscarinic receptor subtypes present in guinea-pig cerebral cortex, myocardium and salivary glands has been examined. The (+) enantiomer is more potent in all assays and exhibits a greater selectivity than the (-) enantiomer for the different receptor subtypes. As a consequence, the enantiomeric potency ratio varies from ca. 400 (cortical 'M1' receptors) to ca. 50 (cardiac receptors). In functional assays in vitro in the rabbit vas deferens and rat atria, the affinity constants and enantiomeric potency ratios for the two isomers agree with those found for the appropriate muscarinic receptor subtype in binding assays. A high enantiomeric potency ratio, 180, is found in vivo for the ability of the telenzepine enantiomers to inhibit the production of lesions in the modified Shay rat preparation. The data are compatible with the blockade of M1 receptors by (+)-telenzepine being responsible for this action of telenzepine and would tend to exclude the possibility that the anti-ulcer action of telenzepine is mediated via a muscarinic or non-muscarinic action of the (-) enantiomer.

Platinum-folate compounds: synthesis, properties and biological activity.

Cis-diamminediaquaplatinum(II)-ion, the biologically active form of the anticancer agent Cisplatin, reacted readily with tetrahydrofolate at pH 7 and 37 degrees C to produce a stable complex. The reaction was monitored spectrophotometrically by the change in absorbance maximum from 298 nm (tetrahydrofolate) to 275 nm (complex); occurrence of isobestic points at 282 and 327 nm indicated that a single product was formed. Purity of platinum-tetrahydrofolate, after isolation in ca. 70% yield, was established by TLC and HPLC. Elemental analysis, absorbance spectra at various pH values and nmr spectra provided evidence that the diammine platinum moiety was bridged across the N-5 and N-10 positions of tetrahydrofolate. Complexation also occurred with 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, Methotrexate and aminopterin, but not with folate or 7,8-dihydrofolate. Biological implications of these observations have been investigated. Intracellular folates in L1210 cells have been identified and quantitated via reverse phase HPLC (C18 column; tetrabutylammonium phosphate as the pairing ion) and changes in the levels of these compounds, after exposure of cells to Cisplatin, have been measured. Platinum derivatives of tetrahydrofolate or other reduced folates were not found, but there was a decrease in the level of 5,10-methenyltetrahydrofolate, accompanied by an increase in 5-formyl and 10-formyltetrahydrofolate (and perhaps tetrahydrofolate). The chemical interaction of the diaqua form of Cisplatin with Methotrexate resulted in decreased uptake of the latter by L1210 cells. The platinum complex of tetrahydrofolate was a reasonably good inhibitor (Ki = 4 microM) of L1210 dihydrofolate reductase and of the folate transport system (50% inhibition at ca. 200 microM) of L1210 cells.