Molecular hybridization is a recent strategy based on the covalent fusion of two or more pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides (e.g. enkephalins, deltorphins and endomorphins) have been developed, and γ-aminobutyric acid agonists have also been designed for neuropathic pain control. In addition, a number of hybrid compounds have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity, which may be further developed as potential antiepileptic drugs. Moreover, several hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing hybrid compounds including an antioxidant moiety, which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.
Keywords: Alzheimer's disease; Parkinson's disease; central nervous system; epilepsy; molecular hybridization; pain.
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