Analogues of methyllycaconitine (MLA) as antagonists of nicotinic receptors.

摘要

Nicotinic acetylcholine receptors (nAChRs) are very important in the physiology of the human body. They are involved in transmitting nerve signals and in the control of neurotransmitter release. Among the physiological functions affected are memory, learning and pain transduction. Several different subtypes of receptors are known, and they appear to have distinct physiological functions. Even though a variety of ligands for nicotinic receptors is known, there is a lack of ligands binding selectively to specific subtypes. Such ligands would be very useful as pharmacological tools in determining the roles of specific subtypes as well as in manipulations of the activity of those subtypes.; One ligand has caught the eye of researchers due to its selectivity and high potency towards α7-receptors. This is methyl lycaconitine (MLA), which is a norditerpenoid alkaloid isolated primarily from plants of Delphinium species. MLA is the most potent non-protein antagonist of the α7-subtype of nicotinic receptors, and is therefore ideal for studies on structure-activity relationships. The main drawback is the complexity of the molecule, which makes synthesis of very similar analogues very difficult. Therefore, most work in this area has been directed at simpler analogues.; Initially a series of ring E analogues of MLA had been prepared. The biological results from that series showed promise for the prospects of developing other analogues with even higher potency towards α3β4* receptors. The synthesis of another series of analogues was in progress and the completion of that series is described as well as the synthesis of four additional series of analogues. A problem with one step in the initial synthesis was solved, and finally, a ring DE analogue of MLA was designed and its synthesis carried out.; The results obtained from biological assays indicate high potency towards α3β4* receptors, even exceeding that of MLA. Although MLA is selective towards α7-subtype of receptors, it is still quite potent towards α3β4*. However, all the analogues, that have been tested so far, have been found to be non-competitive antagonists. This means that these analogues are not binding to the agonist binding site on the receptor, but are affecting the receptor in some other way.