21 Concomitant activation of G-protein coupled receptors (GPCR) and sigma1 receptor (Sig1R): a novel pharmacological concept in treatment of Alzheimer's disease (AD)

Abstract

The M1 muscarinic agonists AF102B (Evoxac: prescribed in Sjogren’s syndrome) and AF267B {successful in Phases I and IIa (Sjogren’s syndrome)} are effective cognitive enhancers and disease modifiers with a wide safety margin. Notably, i) AF102B decreased CSF Abeta in Alzheimer’s disease (AD) patients (Nitsch et al, Ann Neurol 2000); ii) AF267B rescued cognitive deficits and decreased Abeta42 and tau pathologies in 3xTg-AD mice (Caccamo et al, Neuron, 2006); and iii) in transgenic mice overexpressing human alpha-synuclein, AF102B and AF267B decreased brain alpha-synuclein aggregates (A. Fisher, E. Mazliah, B. Hutter-Paier, D. Havas, M. Windisch, ADPD 2011). Thus the M1 muscarinic GPCR appears to be a pivotal target for treatment of AD, Parkinson’s disease (PD) and Lewy body dementia (LBD). We have also hypothesized that concomitant activation of such a GPCR and the molecular chaperone Sig1R may have broader therapeutic implications in AD and related diseases. To achieve such combined activity we designed a low MW (357.5) compound, AF710B. This compound shows a novel mechanism of enhancing neuroprotection and cognition via Sig1R activation and M1 muscarinic modulation, but not resembling sigma1, M1 muscarinic (allosteric or orthosteric) and dual sigma1/M1 agonists, respectively. The effects of AF710B at low concentrations in vitro against neurodegeneration, oxidative stress, Abeta, Tau-phosphorylation and GSK-3beta activation translate into down-regulation of the apoptotic protein Bax and mitochondrial dysfunction, up-regulation of antiapoptotic Bcl2 and possible modulations of downstream kinases (e.g. PKC, PKB, GSK-3beta). AF710B has an exceptional pharmacology being an excellent cognitive enhancer in rats (at 1-30 and 10-100 mcg/kg, po in trihexyphenidyland in MK801-induced passive avoidance impairments, respectively). Furthermore, AF710B is devoid of side effects, having an unprecedented safety margin 50000 (po). In summary, while M1 agonists can alter pathologies in AD, PD and LBD, the unique profile of AF710B indicates widespread therapeutic advantage, inter alia, also on mitochondrial dysfunctions in these and other protein-aggregation related diseases. 22 NPT002: A NOVEL APPROACH FOR TARGETING -AMYLOID AND TAU AGGREGATES IN ALZHEIMER’S DISEASE