Joseph W. Kosh

Synthesis of Substituted 2-Aminopyrrole Analogs of Lidocaine I

The synthesis, local anesthetic, and antiarrhythmic properties of nine 2-diethylaminoacetamido-3-cyano-4-methyl-5-substituted pyrroles are described. All compounds showed local anesthetic activity by the guinea pig wheal test and antiarrhythmic activity for chloroform-induced ventricular arrhythmias in mice.

Synthesis of novel tellurium containing analogues of choline and acetylcholine and their quantitation by pyrolysis-gas chromatography-mass spectrometry

Methods for the synthesis and quantitation of the novel choline analogues, telluronium choline and acetyltelluronium choline, are described. An assay procedure utilizing pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) with cold trapping was developed with [2H4]telluronium choline and [2H4]acetyltelluronium choline as internal standards. The telluronium compounds were ion-pair extracted from tissue with dipicrylamine, washed with 2-butanone, and pyrolyzed prior to GC-MS analysis. The compounds were monitored using selected ion monitoring at m/z 232 and m/z 190 for acetyltelluronium and telluronium choline, respectively, and at m/z 236 and m/z 194 for the analogous deuterated internal standards. The assay was linear over a range of 20 pmol-20 nmol of compound taken through the assay.

A Comparison of the Cholinergic Activity of Selected H2-Antagonists and Sulfoxide Metabolites

Famotidine and selected H2-antagonists were evaluated with respect to toxicity and selected pharmacological activities. When administered intraperitoneally to mice at a dose equivalent to 10 times their respective H2-antagonist ED50 values, no deaths were observed. Similarly, no alteration in brain ACh concentrations or overt pharmacological effects were noted. However, at 400 mg/kg, ranitidine produced 89% lethality, followed by cimetidine (11%) and famotidine. Only cimetidine and famotidine at this dose significantly elevated brain acetylcholine levels. These results do not correlate with the in vitro data, where ORF-17578 and ranitidine were the most potent entities with respect to acetylcholinesterase inhibition (∼1–2 × 10−6M), followed by nizatidine > cimetidine > famotidine. The sulfoxide metabolites of ranitidine and cimetidine were approximately one-tenth as potent as their parent compounds with respect to inhibition of acetylcholinesterase. Direct muscarinic stimulation or potentiation of acetylcholine-induced contraction in ileal tissue was not observed for any of the H2-antagonists.

Selected cardiovascular and central properties of three lidocaine analogs.

Three analogs of lidocaine (benzyl carbamyl, benzyl nitrile and methyl nitrile) were synthesized and examined for cardiovascular and central activity. The benzyl carbamyl analog was more potent than lidocaine in lowering blood pressure but possessed only slight local anesthetic, antiarrhythmic and CNS-depressant activity. At 40 mg/kg the benzyl nitrile derivative was superior to lidocaine in protecting against chloroform-induced arrhythmias. The methyl nitrile analog was less active than the benzyl nitrile analog in most parameters examined. The benzyl nitrile derivative and lidocaine had similar potencies on blood pressure depression, local anesthetic activity and ability to protect against calcium chloride-induced arrhythmias. Unlike the benzyl carbamyl derivative both lidocaine and the benzyl nitrile compounds appear to depress the cardiovascular system via a common mechanism.

Strong inhibition of estrone-3-sulfatase activity by pregnenolone 16α-carbonitrile but not by several analogs lacking a 16α-nitrile group ☆

In recent years, development of potent inhibitors for estrogen sulfatases has become an actively pursued strategy for chemoprevention and/or chemotherapy of estrogen-dependent human breast cancers. We report here our findings that pregnenolone 16α-carbonitrile (PCN) is a potent inhibitor of estrone-3-sulfatase activity of rats and also humans. PCN inhibited in a concentration-dependent manner the desulfation of estrone-3-sulfate catalyzed by liver microsomal and nuclear fractions of female Sprague–Dawley rats. The inhibition of estrone-3-sulfatase activity in these two subcellular fractions showed a biphasic pattern, with a highly sensitive phase seen at 78 nM to 1.25 μm of PCN followed by a markedly less-sensitive phase at > 2.5 μm of PCN. Interestingly, several of PCN′s structural analogs without a 16α-nitrile group showed little or no inhibitory effect on rat liver microsomal E1-3-sulfatase activity. Double-reciprocal analysis showed that the inhibition of rat liver microsomal E1-3-sulfatase activity by PCN was essentially competitive in nature. When microsomes from six human term placentas were tested for their E1-3-sulfatase activity, PCN showed a similar biphasic inhibition of placental E1-3-sulfatase. Likewise, several of its structural analogs showed little or no inhibitory effect on placental E1-3-sulfatase activity. Computational analysis of the D-ring structure of PCN and other structurally similar analogs used in the study suggests that the potent sulfatase-inhibiting activity of PCN may be partly due to its unique steric orientation and size of the 16α-nitrile group. This knowledge may be useful for the rational design of more potent steroidal inhibitors of E1-3-sulfatase by introducing an additional nitrile group to their C16α-position.

BENZYL CARBAMYL ANALOGUE OF LIGNOCAINE: VASODEPRESSOR MECHANISM OF ACTION

1. The benzyl carbamyl analogue of lignocaine [2‐(diethylaminoacet‐amido)‐3‐carbamyl‐4‐methyl‐5‐benzylpyrrole] at an intravenous dose of 4 mg/kg caused a blood pressure decrease of 54 mmHg.