G. Renzi

Carbonic anhydrase inhibitors: topical sulfonamide antiglaucoma agents incorporating secondary amine moieties

Reaction of aromatic/heterocyclic sulfonamides possessing free amino, imino or hydrazino moieties with 7-chloro-4-chloromethylcoumarin afforded a series of N-[(7-chloro-4-coumarinyl)-methyl]- derivatives which showed effective inhibition of three carbonic anhydrase (CA) isozymes. Topical application within the rabbit eye of some of these compounds led to effective intraocular pressure lowering due to CA inhibition within the ocular tissues, and reduced aqueous humor production.

Inhibition of [3H]naloxone binding in homogenates of rat brain by eseroline, a drug, with analgesic activity, related to physostigmine

effectively blocked by metergoline. A receptor mediated reaction might be expected to show a saturation effect. However, in our experiments, 5-HT at M does not h a h s u c h an effect. It is possible that stimulation of (Na+-K+)-ATPase by 5-HT is mediated by more than one mechanism, as has been envisaged by us for the activation of (Na+-K+)-ATPase by noradrenaline (unpublished observations). Further studies on this receptor-mediated 5-HT stimulation of (Na+-K+)-ATPase should provide an insight into the mechanism by which 5-HT generates its depressant action on cerebral cortical neurons. The authors are grateful for the excellent technical assistance of Mr. K. C. Moore. This investigation was supported by the Medical Research Council of Canada. May 30, 1979

Eseroline: a new antinociceptive agent derived from physostigmine with opiate receptor agonist properties. Experimental in vivo and in vitro studies on cats and rodents.

We report that eseroline, until now thought devoid of any biological action, is a potent antinociceptive agent. Its antinociceptive action is stronger than that of morphine in all tests studied and, though shorter lasting than that of the latter, has a latency of only a few minutes by subcutaneous route. Eseroline, like morphine and enkephalins, inhibits the electrically evoked twitches of the mouse vas deferens and of the guinea-pig ileum. Eseroline, moreover, releases 5-hydroxytryptamine from cat brain cortex in way similar to that of morphine and physostigmine.

Reversible inhibition of acetylcholinesterase by eseroline, an opioid agonist structurally related to physostigmine (eserine) and morphine

The action of eseroline--(3aS,8aR)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indo l-5-ol--salicylate was tested on preparations of ChE from different sources and on the longitudinal muscle of guinea-pig ileum. While eseroline is eseroline is extremely weak-acting on horse serum BuChE (Ki = 208 +/- 42 microM), it is a rather strong competitive inhibitor of AChEs, its Ki being 0.15 +/- 0.08 microM, 0.22 +/- 0.10 microM and 0.61 +/- 0.12 microM in electric eel, human RBC and rat brain, respectively. Eseroline inhibitory action in AChE in independent of the duration of pre-incubation and appears fully developed in less than 15 sec. This action is also rapidly reversible; after pre-incubation followed by dilution, maximum enzymic activity is regained within 15 sec. The electrically-evoked contractions of the longitudinal strip were inhibited by concentrations of eseroline in the range 0.2-15 microM, while they were increased by concentrations over 20 microM. In the same preparation, without electrical stimulation, but in the presence of naloxone, eseroline induced contractions at concentrations higher than 5 microM. This effect was antagonized by atropine. The inhibitory activity of eseroline parallels, as regards selectivity, potency and kinetics, that of the phenolic anticurare agent edrophonium, while it differs markedly from that of physostigmine.

In-vitro and in-vivo protection of acetylcholinesterase by eseroline against inactivation by diisopropyl fluorophosphate and carbamates

The protective action of eseroline—(3aS, 8aR)‐l,2,3,3a,8,8a‐hexahydro‐l,3a,8‐rimethyl‐pyrrolo[2,3‐b]indol‐5‐ol—salicylate against (DFP) diisopropyl fluorophosphate and carbamate poisoning of cholinesterases (ChEs) has been examined in‐vitro with human erythrocytes and purified preparations of electric eel acetylcholinesterase (AChE) and of horse serum butyrylcholinesterase (BuChE), and in‐vivo using mice. Eseroline afforded 50% protection (ED 50) of erythrocyte AChE against inactivation by 1 μM DFP, physostigmine or neostigmine, at concentrations of 4.3, 22 and 23.5 μM, respectively, while for eel AChE protection against 10 and 30 μM DFP, 0.3 and 1 μM physostigmine and 1 μ m neostigmine the eseroline ED 50 values were 0.3, 0.4. 0.7, 1.9 and 5.6 μM, respectively. On the other hand, up to 0.3 mM eseroline did not appreciably affect the inhibitory action of the same drugs on horse serum BuChE. Eseroline concentrations in the range 0.1‐1 mM were able to reactivate 20‐42% of erythrocyte AChE previously inhibited by 100 μM physostigmine, but failed to reactivate the DFP (10 μM)‐pretreated enzyme to any extent. Finally, eseroline salicylate injected into mice (10 mg kg−1 s.c.) protected an average of 82 and 26% of the animals against lethal doses of DFP (7mg kg−1 s.c.) and physostigmine sulphate (1 mg kg−1 i.p.) respectively, which were administered 15 min later. These results indicate that the protective activity of eseroline correlates well with its own anti‐ChE profile, and that the effectiveness of the protection depends largely on the rate of AChE inhibition by the agents used to inactivate the enzyme.

Intramolecular ring-stacking interaction between caffeine and bis(1,10-phenanthroline)copper(II) ion: 1H NMR and calorimetric investigations

Abstract The interaction occuring in aqueous solution between caffeine and the bis(1,10-phenanthroline)copper(II) cation has been investigated. 1 H NMR spectroscopy allowed us to establish that no coordinative bonding occurs between the copper atom and the caffeine molecule, the interaction being therefore of ring-stacking type. Calorimetric and thermodynamic data are also reported and discussed in the light of the relevance of this type of interactions especially for biomolecules.

The structure and action of eseroline: A new antinociceptive drug

Abstract The synthesis of eseroline and its salts has been performed in an attempt to clarify the relationship between structure and activity of physostigmine and eseroline. Eseroline as a free base is quite unstable and is easily oxidized [1], whereas its salts with acids like salicylic, fumaric, tartaric etc. are stable even in solution in presence of antioxidant agents. The structure, conformation and electronic properties of eseroline have been investigated through 1H and 13C NMR, mass spectrometry, UV and IR spectroscopies. All of these measurements show that the structure is similar to that of physostigmine. The 13C NMR spectrum is closely related to that of physostigmine, thus allowing to safely establish the same spatial arrangement of the dipirrolic moiety in both molecules. Eseroline has antinociceptive activity comparable in potency to that of morphine. At variance with physostigmine, eseroline shows high affinity for the opioid receptor sites as demonstrated by its ability in inhibiting stereospecific [3H]-naloxone binding in homogenates of rat brain [2]. The groups interacting with opioid receptor sites are the phenolic ring and the pyrrolidine nitrogen which show the same distance between the phenolic ring and the piperidine nitrogen of the morphine molecule. Eseroline, although derived from physostigmine by hydrolysis of N-methylcarbamoil group, is also structurally related to morphine. The methylcarbamate group present in physostigmine differentiates this drug from eseroline and is responsible in determining the well known indirect cholinomimetic activity.