Editorial [ Hot Topic : Receptor Dimerization and Bivalent Ligands, an Emerging Topic for Drug Design (Guest Editor: Dr. Ao Zhang) ]

The rapid advances of molecular biology, neuropharmacology, anatomy, gene cloning, and recombinant DNA techniques have unravelled our understanding of a large number of receptors. An increasing number of secondary and tertiary structures of these receptors are being disclosed. Further, an increasing number of receptors have been reported recently to dimerize or oligomerize, which opens a new vistas to receptor researchers. The biology, pharmacology, function and utility of such phenomenon, as well as how receptor dimerization/ oligomerization can guide drug design and discovery are being extensively investigated. In this issue of Current Topics in Medicinal Chemistry, we highlight several aspects of the receptor dimerization and bivalent ligands of the most developed receptors by collecting comprehensive reviews from several experts working in this emerging field. In the first article, Zhang and Kan discussed the most recent advances in the receptor dimerization phenomenon. Several key elements regarding this process are postulated and discussed. The utility of this common feature of receptors to guide drug design and development are confirmed, and the critical considerations leading to the successful discovery of bivalent drugs are presented. Decker and Lehmann reviewed bivalent ligands developed for dopamine and serotonin receptors, as well as their respective transporters reported within the last two decades. They pointed out that increased potency, selectivity and CNS penetration for 5-HT1B/1D receptor agonists could be achieved with the bivalent ligands. Bivalent dopamine receptor agonists and antagonists can exhibit selectivity profiles very different from their monomeric analogues without loss in potency. Nowak presented the progress of bivalent ligands for probing the membrane targeting C1 subdomains of protein kinase C (PKC), a family of ubiquitously expressed signal transducing proteins. Novel and conventional subfamilies of PKC have two C1 domains, C1A and C1B. Bivalent PKC ligands are designed to activate simultaneously both C1 domains. Many bivalent ligands displayed 1-2 orders of magnitude higher potency than their monovalent congeners with the “dimeric” ligands containing 10-14 carbon spacers being the most effective. Peng and Neumeyer presented a comprehensive review of the most developed kappa(κ) opioid receptor bivalent ligands. κ Agonists and antagonist ligands such as norBNI and BNI have been used as tools to elucidate the κ receptor characteristics. Bivalent ligands may also be effective analgesics although none have this far been used clinically. Structure-activity relationships and molecular modeling has led to the development of a more potent and selective κ antagonist (GNTI). In addition, novel hetero-bivalent ligands with high mixed κ/μ or mixed κ/δ affinity and intriguing pharmacological properties are also discussed. It is pointed out that such bivalent ligands have great potential as novel analgesics with fewer adverse side effects, and as alternative treatment for drug abuse. Haviv, Wong, Silman and Sussman commented on the bivalent ligands derived from Huperzine A as an acetylcholinesterase (AchE) inhibitors. The naturally occurring alkaloid Huperzine A (HupA) has been used for centuries as a Chinese folk medicine from its source plant Huperzia Serrata. Its pharmacological profile has now led to its use as a promising drug for the treatment of Alzheimer's disease. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site of AChE, initiating the development of Huperzine A-based bivalent ligands. Extensive studies have been conducted by these authors as well as by others, and are summarized in this manuscript. The advantages and disadvantages of such a bivalent ligand approach are also presented.