The Current Status of Drug Discovery for the Oxytocin Receptor.

The oxytocin receptor plays a significant role in peripheral regulation of parturition and lactation. Given this important role, multiple drug discovery programs have been conducted to develop agonists and antagonists for peripheral activity. The role of the oxytocin receptor in the central nervous system is also significant, promoting social interaction, trust, and empathy in humans. As such, molecules that can access the central nervous system and target the oxytocin receptor are of significant interest. Due to the role of the oxytocin receptor in regulating social function and psychological well-being, agonists of this receptor have considerable promise for the treatment of numerous neuropsychiatric conditions. The poor pharmacokinetic properties and blood-brain barrier penetration of peptide-based molecules means nonpeptide compounds have more commonly been the focus for central nervous system activity. This chapter aims to summarize the current standing of peptide and nonpeptide drug discovery for antagonists and agonists of the oxytocin receptor and focusses on centrally active nonpeptidic agonists.

Differences in local anaesthetic and antiepileptic binding in the inactivated state of human sodium channel Nav1.4.

Voltage-gated sodium channels play a vital role in nerve and muscle cells, enabling them to encode and transmit electrical signals. Currently, there exist several classes of drugs that aim to inhibit these channels for therapeutic purposes, including local anesthetics, antiepileptics and antiarrhythmics. However, sodium-channel-inhibiting drugs lack subtype specificity; instead, they inhibit all sodium channels in the human body. Improving understanding of the mechanisms of binding of existing nonselective drugs is important in providing insight into how subtype-selective drugs could be developed. This study used molecular dynamics simulations to investigate the binding of the antiepileptics carbamazepine and lamotrigine and the local anesthetic lidocaine in neutral and charged states to the recently resolved human Nav1.4 channel. Replica exchange solute tempering was used to enable greater sampling of each compound within the pore. It was found that all four compounds show similarities in their binding sites within the pore. However, the positions of the carbamazepine and lamotrigine did not occlude the center of the pore but preferentially bound to homologous domain DII and DIII. The charged and neutral forms of lidocaine positioned themselves more centrally in the pore, with more common interactions with DIV. The best localized binding site was for charged lidocaine, whose aromatic moiety interacted with Y1593, whereas the amine projected toward the selectivity filter. Comparisons with our previous simulations and published structures highlight potential differences between tonic and use-dependent block related to conformational changes occurring in the pore.