Natural enhancers of nicotinic functions devoid of anticholinesterase activity and non-classical nicotinic post-synaptic modulators: a pharmacological approach to molecular interactions

• Grant number: 01/11274-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: December 01, 2002
• End date: February 29, 2008
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Antonio José Lapa
• Grantee: Antonio José Lapa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Taking into account the complexity of the cholinergic transmission at central and peripheral synapses of the CNS, it is expected that specific pharmacological modulation will require selective ligands to either stimulate or to block the synaptic function without adverse effects elicited in other cholinergically innervated organs. This class of drugs has been intensively searched in nature, the animal toxins and plant derived chemicals being the most useful substrates (Taylor et al., 1998; Harvey, 2000). For the present proposal, nine (9) probes were selected from previous experiments screening for nicotinic cholinergic interactions: three natural compounds purified from Brazilian medicinal plants (I-bebeerine from Chondodrendum plathyphylum Miers and 2 macrocyclic molecules isolated from Cuphea carlhagenensis (Jacq) Macbr under final chemical identification); two semi-synthetic derivatives of I-hyoscyamine (exo-phenthonium and endo-phenthonium) and four derivatives of procainamide, respectively the [2-(4-methylsulphonyl) or 2-(4-bromo) or 2-(4- butyl) or 2-(4- hexyl) derivatives of - benzamido)ethyl]-benzyldimethylammonium bromide, obtained after QSAR (Quantitative Structure Activity Relationship) studies and shown to be endowed with exacerbated nicotinic cholinergic activity at peripheral synapses. Some of these probes enhanced cholinergic activity by either increasing acetylcholine release at peripheral synapses (exo-Phenthonium) or reversing the neuromuscular blockade produced by curare (the Cuphea's macrocyclic compounds). None of them, however, depolarized the post-junctional membrane or presented anticholinesterase activity. The Chondrodendron's alkaloid /-Bebeerine had a dual action at the end-plate activating the muscle nicotinic receptor (nAChR) before its final blockade. Finally the procainamide derivatives synthesized after its anesthetic / antiarrythmic properties showed a higher affinity for the nAChR than for the sodium channel. At high doses ali the selected probes but Cuphea's compounds, inhibited the neuromuscular transmission. (AU)