Immunosuppressive Compoundswas added, and the flask was tightly closed and left at room temp.At the end of the required reaction time the solvent was removed under reduced pressure, and the product was purified as described in Table I.Method C.-In a flask as above and using a condenser, d-pilocarpine (0.02 mole) was dissolved in Me»CO (10 ml) with constant stirring while heating to about 50°. A freshly prepd soln of 0.025 mole of the halo organic reagent in 10 ml of Me2CO was then slowly added and the mixt was heated to reflux for 30 min (reflux was not necessary for 9). After cooling, the soln was transferred to a dry flask with 20 ml of dry Me2CO and kept tightly closed at room temp for the required period. The Me2CO was then removed under reduced pressure above a H20 bath, and the residue was dried. For purification of the products see Table I. In the case of 23, d-pilocarpine was added to a suspension of the halo org reagent in dry Me2CO at reflux temp, and the product was collected by filtration.Method D.-In a flask equipped as above, a soln of halo org reagent (0.02 mole) in 2-methoxyethanol (20 ml) was heated to 50°with stirring; then a soln of d-pilocarpine (0.02 mole in 25 ml of the same solvent) was added dropwise. The mixt was heated with stirring to 80°for 30 min and left tightly closed at room temp for the required period. The solvent was removed at 80°under reduced pressure, and the residue was dried over PA. For 4 no heating was required and the molar ratio was 1.5:1. Whenever min amounts of the HBr of the pilocarpine were obtd as a side product, the sepn from the quaternary compds was accomplished from an aq soln at pH 7.5. The free pilocarpine was extd with CHClg leaving the quaternary compd in the aq layer which was then lyophilized.Compd 25 (R = p-BrC6H5C6HOHCH2).-3-(iV-p-Bromophenacy 1 )-d-pilocarpinium bromide (20) (0.24 g, 5 X 10-4 mole) was dissolved in MeOH (30 ml), and NaBH4 (0.12 g, 3 X 10~3 mole) was added and stirred for 1 hr. The soln was then filtered and adjusted to pH ~7 (with HC11:4). The solvent was removed under reduced pressure, and the residue was dried overnight in a desiccator over PA. This residue was then dissolved in a min quantity of abs EtOH and filtered. After evapn of the solvent, the yellowish product (0.29 g, 93%) was redissolved in abs EtOH, decolorized with activated C (Darco G 60; 15 min at

No abstract

Molecular orbital calculations by the CNDO/2 method are used to study the potential energy surface for the stretching and rupturing of the CH2-OAc bond in a model cephalosporin structure, 7-amino-3-(acetoxymethyl)-3-cephem. The bond is easier to stretch and break when a nucleophilic group is in the vicinity of or attached to the beta-lactam carbonyl carbon (C8). The rate of acylation by a beta-lactam antibiotic at the receptor sites in bacterial cell-wall enzymes will be enhanced by a suitable leaving group at the 3' position. An orientational specificity is predicted for the direction of departure of the leaving group. Regardless of the direction the nucleophile approaches C8, the CH2-OAc bond is easiest to break when the acetate group departs from the alpha face of the molecule.

No abstract

At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.