1-Phenyl-3-azabicyclo[3.1.0]hexane derivatives as new ligands for sigma receptors

n/

New developments in opioid receptors ligands

En los últimos veinte años se ha llevado a cabo una intensa investigación sobre la búsqueda de agonistas y antagonistas selectivos de cada subtipo de receptores opiáceos. Recientemente, se han sintetizado nuevos derivados benzomorfánicos y compuestos con restos ciclopropilmetílicos sobre N-l que muestran alta afinidad y selectividad por los receptores K . Los compuestos MPCB y CCB se han seleccionado como agonistas específicos La afinidad de CCB es dos veces mayor que la del compuesto USO,488H. De estos compuestos se han derivado interesantes compuestos con estructura de peptidoheterocido y se han obtenido importantes informaciones sobre los procesos de binding a los receptores K.Relevant developments have been achieved in the last twenty years in the search for opioid agonists and antagonists with selectivity for each receptor subpopulation. Recently, new benzomorphan derivatives have been synthesized and compounds with substituted cyclopropylmethyl functionalities at N-l position showed high affinity and selectivity for K opioid receptor subpopulations. MPCB and CCB were selected as specific K agonists. The affinity ofCCB was two-fold the USO,488H one. Mixed peptide-heterocyclic compounds have been derived from these compounds and important informations on binding processes of K ligands have been obtained

Investigaciones actuales en ligandos de receptores opiáceos

Relevant developments have been achieved in the last twenty years in the search for opioid agonists and antagonists with selectivity for each receptor subpopulation. Recently, new benzomorphan derivatives have been synthesized and compounds with substituted cyclopropylmethyl functionalities at N-l position showed high affinity and selectivity for K opioid receptor subpopulations. MPCB and CCB were selected as specific K agonists. The affinity ofCCB was two-fold the USO,488H one. Mixed peptide-heterocyclic compounds have been derived from these compounds and important informations on binding processes of K ligands have been obtained.En los últimos veinte años se ha llevado a cabo una intensa investigación sobre la búsqueda de agonistas y antagonistas selectivos de cada subtipo de receptores opiáceos. Recientemente, se han sintetizado nuevos derivados benzomorfánicos y compuestos con restos ciclopropilmetílicos sobre N-l que muestran alta afinidad y selectividad por los receptores K . Los compuestos MPCB y CCB se han seleccionado como agonistas específicos K. La afinidad de CCB es dos veces mayor que la del compuesto USO,488H. De estos compuestos se han derivado interesantes compuestos con estructura de peptidoheterocido y se han obtenido importantes informaciones sobre los procesos de binding a los receptores K

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell-surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target-based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell-surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target-based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids

Nuova Serie di Ligandi Sigma a Struttura Piperazinica e Piperidinica

..

Morphing of ibogaine: A successful attempt into the search for sigma-2 receptor ligands

Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ 2 receptor. Indeed, extensive data support the involvement of the σ 2 receptor in neurological disorders, including Alzheimer’s disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved σ 2 receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective σ 2 receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the σ 2 pK i values of the new compounds, whereas a molecular docking study conducted upon the σ 2 receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ 2 receptor affinity through radioligand binding assay and the results confirmed the predicted high μM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved σ 2 receptor binding capabilities

1,3-Diossolani e analoghi aperti come nuovi ligandi per il recettore Sigma

..

Synthesis and pharmacological evaluation of 1-benzylpiperazine and 4-benzylpiperidine as potent sigma ligands.

It is now well established that sigma receptors are an independent class of receptors expressed in peripheral organs and in the central nervous system. There are at least two identified subtypes, namely sigma1 and sigma2, with distinct functional roles and different pharmacological characteristics. On the basis of their neuroregulative and neuropotective functions sigma1 agents could be potentially used for the treatment of depression and psychiatric disorders. The finding of high concentration of sigma2 receptors in neuronal and non-neuronal tumor cell lines provides evidence of a possible role in anticancer therapy. A variety of chemically unrelated compounds is able to bind sigma receptors, however only few bind with high affinity and selectivity to sigma receptor subtypes. This situation has given new impulse to medicinal chemists for the search of new and more selective ligands.We have recently reported that substituted 1-benzylpiperazine and 4-benzylpiperidine derivatives were shown to be high-affinity sigma ligands (Ki in the nanomolar range) with a slight preference for sigma1 over sigma2 receptors1-2. With the aim to improve sigma1/sigma2 selectivity we have studied the effect of some substitutions of the oxygen atoms on the 1,3-dioxolane ring by synthesizing 1,3-oxathiolane, 1,3-dithiolane, tetrahydro-furan, cyclopentanone and cyclopentanol derivatives as depicted below. A spiro derivative was additionally prepared and tested to study the influence of the two aromatic rings on receptor affinity. The preliminary pharmacological results show a significant improvement of sigma1 selectivity for compound A. Structure-activity relationship will be extensively discussed during the congress