Ligand tethering by ion-exchange for the immobilization of homogeneous catalysts

A Rh phosphine complex, derived from the Wilkinson’s catalyst, has been immobilized by ion-exchange on the ammonium form of a Al-MCM-41 sample. Ammonium ions have been exchanged by cholamine ions, which act as an amine ligand, and then the Wilkinson’s catalyst has been immobilized by substitution of a phosphine ligand by the anchored amine. This is a novel immobilization procedure, as a ligand, instead of the whole complex, is tethered to the support by ion exchange. The obtained hybrid catalyst has been characterized by Elemental Analysis, DRIFTS and XPS. The quantitative exchange of ammonium by cholamine and coordination of Rh to amines has been observed. Most of the anchored Rh is considered to be coordinated to the ligand tethered to the support and a small proportion seems to be interacting with the protonated ligand or with the support surface. The catalyst has been tested in the hydrogenation of cyclohexene and in the hydroformylation of 1-octene. In the first case the catalyst is active and reusable, while a strong Rh leaching takes place in the second one.

Muscle-Type Nicotinic Receptor Blockade by Diethylamine, the Hydrophilic Moiety of Lidocaine

Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs), this work was aimed to determine the inhibitory effects of diethylamine (DEA), a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh) in a dose-dependent manner (IC50 close to 70 μM), but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel) was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM) domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3, and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC) domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and α-δ and interphases, likely because of its larger size. Together, these results indicate that DEA mimics some, but not all, inhibitory actions of lidocaine on nAChRs and that even this small polar molecule acts by different mechanisms on this receptor. The presented results contribute to a better understanding of the structural determinants of nAChR modulation.