A Convenient Synthesis of 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoic Acid

Barker D., McLeod M.D., Brimble M.A., Savage G.P.

The synthesis of four novel ABE ring analogues of methyllycaconitine (MLA) is reported, employing olefin metathesis as the key step for appending the seven-membered B ring onto an AE bicyclic ring system. This strategy allows the stereodivergent synthesis of ABE ring analogues in which the stereochemistry of the AB ring junction is well defined. The compounds are designed as ligands to study binding and function of the α7-nAChR.

Bryant D.L., Free R.B., Thomasy S.M., Lapinsky D.J., Ismail K.A., McKay S.B., Bergmeier S.C., McKay D.B.

The development of new agents that selectively interact with subtypes of neuronal nicotinic receptors (nAChRs) is of primary importance for the study of physiological processes and pathophysiological conditions involving these receptors. Our laboratory has evidence that simple ring E analogues of methyllycaconitine (MLA) act as antagonists to bovine adrenal alpha3beta4* nAChRs. The following studies were designed to characterize the concentration-response effects of several ring E analogues of MLA in order to assess structural requirements involved with their inhibitory activity on bovine adrenal alpha3beta4* nAChRs. Ring E analogues with various substitutions on the ring E nitrogen were tested for their ability to inhibit nicotinic stimulated adrenal catecholamine release and [3H]epibatidine binding to a bovine adrenal membrane preparation. Several N-alkyl derivatives inhibited secretion with IC50 values in the low micromolar range. The N-phenpropyl analogue was the most potent of the analogues tested (IC50, 11 microM) on adrenal secretion. Competition binding studies suggest a noncompetitive interaction of the analogues with bovine adrenal nAChRs. These studies identify several structural features of ring E analogues of MLA which significantly affect their inhibitory activity on bovine adrenal alpha3beta4* nAChRs.

Atta-ur-Rahman, Iqbal Choudhary M., Atta-ur-Rahman, Iqbal Choudhary M., Atta-ur-Rahman, Iqbal Choudhary M.

Kraus G.A., Dneprovskaia E.

An efficient procedure for attaching the methylsuccinimidobenzoate ester unit to an ABE ring segment of methyllycaconitine is described.

Baillie L.C., Bearder J.R., Li W., Sherringham J.A., Whiting D.A.

Hardick D.J., Blagbrough I.S., Cooper G., Potter B.V., Critchley T., Wonnacott S.

Methyllycaconitine (MLA, 1) is a novel, potent probe for mammalian and insect nicotinic acetylcholine receptors (nAChR) and displays remarkable selectivity toward neuronal [125I]-alpha-bungarotoxin (alpha BgTX) binding sites that correspond to alpha 7-type nAChR in mammalian brain. We have shown that, among a number of selected norditerpenoid alkaloids, elatine (2) and nudicauline (3) are equipotent with, or better than, MLA (1) in binding to brain [125I]-alpha BgTX binding sites, with IC50 values of 6.1, 1.7, and 7.6 nM, respectively. The 2-((S)-methylsuccinimido)benzoyl moiety of these ligands is crucial for high-affinity binding, whereas structural modifications to the norditerpenoid core of the ligand can be tolerated without loss of activity or selectivity. In addition to MLA (1), elatine (2), and nudicauline (3), we have examined lycoctonine (4), inuline (6), lappaconitine (7), N-desacetyllappaconitine (8), delsoline (10), delcorine (11), deltaline (12), condelphine (13), and karacoline (14). This study therefore extends the range of norditerpenoids, other than MLA, which can be used to probe this important class of nAChR. All 12 alkaloids were assessed for activity at [3H]nicotine binding sites which are considered to represent alpha 4 beta 2 nAChR. Furthermore, the 1H and 13C NMR spectroscopic data of MLA and elatine have been critically compared.

Jacyno J.M., Harwood J.S., Lin N., Campbell J.E., Sullivan J.P., Holladay M.W.

The norditerpenoid alkaloid lycaconitine (2) was synthesized from lycoctonine (3) and its affinity determined for two neuronal nicotinic acetylcholine receptor subtypes. The structure of 2 was confirmed by a combination of spectroscopic methods.

Kumar P., Dinesh C.U., Pandey B.

The acylphosphoranes 5 formed in a highly selective and sequential manner from the reaction of N-substituted anthranilic acids 1 and N-phenyl(triphenylphosphoranylidene)ethenimine 2 undergo intramolecular Wittig cyclization on the imide carbonyl to afford the pyrrolo- and pyrido[1,2-a]quinolones 6 in moderate to good yields.

Qasem A.M., Rowan M.G., Sanders V.R., Millar N.S., Blagbrough I.S.