Neurogenic potential assessment and pharmacological characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin-Pinoline Hybrids

This work received the honour of being the Cover of the ACS Chemical Neuroscience in its issue of May 20156-Methoxy-1,2,3,4-tetrahydro-β-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.This work was supported by the Spanish Ministry of Economy and Competitiveness (Project SAF2012-31035), the Fundación de Investigacion Mediica Mutua Madrileña Automovilistica (AP103952012), and the CSIC (PIE-201280E074). M.F.R. had a JAE-Predoctoral Contract (Grant JAE-Pre-2009-106) from the Program “Junta para la Ampliación de Estudios” cofinanced by the CSIC and the European Social Fund.Peer Reviewe