Novel Bifunctional Compounds Targeting Nicotine and Dopamine Receptor Subtypes: Synthesis and Pharmacological Investigation

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson’s disease, schizophrenia and drug addiction or drug dependence, may be substantially built on the existence of intramembrane receptor-receptor interactions within receptor mosaics where it is believed that the D2 receptor may operate as the “hub receptor” [1]. In particular, it has been proposed that striatal dopaminergic neurotransmission could be under the control of receptor heteromers containing D2 autoreceptors and non-alpha7 nicotinic acetylcholine heteroreceptors [2]. In an attempt to investigate the biochemical and functional interactions between dopaminergic autoreceptors and nAChRs containing the beta2 subunit, we designed and prepared a group of potential bifunctional derivatives incorporating a D2/D3 agonist moiety and a nicotinic alpha4beta2 antagonist fragment, linked by polymethylene spacers of different length. The new compounds have been biologically characterized for their affinity/specificity/functional profile at the target nACh and D2 receptor subtypes. The synthesis of the designed derivatives and the results of their pharmacological investigation will be presented and discussed. [1] K.Fuxe, D.Marcellino, A.Rivera, Z.Diaz-Cabiale, M.Filip, B.Gago, D.C.S.Roberts, U.Langel, S.Genedani, L.Ferraro, A.de la Calle, J.Narvaez, S.Tanganelli, A.Woods, L.F.Agnati, Brain Res.Rev., 58, 2008, 415-452. [2] D.Quarta, F.Ciruela, K.Patkar, J.Borycz, M.Solinas, C.Lluis, R.Franco, R.A.Wise, S.R.Goldberg, B.T.Hope, A.Woods, S.Ferré, Neuropsychopharmacol., 32, 2007, 35-42.