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CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
Other recently described δ opioid ligands include the naltrexone derivative, naltrindole (Portoghese et al., 1988a and 1988b) and the peptide, deltorphin (Kreil et al., 1989). Naltrindole is a nonpeptide antagonist of the δ opioid receptor reported to have an approximately 100-fold selectivity for the δ relative to the μ opioid receptor. Naltrindole has a substantial affinity advantage over the established δ receptor antagonist, ICI 174,864 (Cotton et al., 1984) in that the Ki, value of naltrindole at the δ receptor (0.1 to 0.3 nM) is over 300-fold lower than that of ICI 174,864.
Selective drug delivery approaches to lesioned brain through blood brain barrier disruption
Published in Expert Opinion on Drug Delivery, 2018
Ligand-targeted drug conjugates have proved promising results to enhance brain delivery. Those are designed in away that the binding of the ligand will be on a region that is not directly involved in the binding of endogenous substrates. A promising example on that is the utilization of OATP/Oatp influx transport systems to enhance drug delivery for ischemic stroke. Statins (e.g. pitavastatin and rosuvastatin) are substrate for OATPs (Oatp1a4) influx system that is expressed on the brain microvascular endothelium [142]. OATP/Oatp isoforms have also a very important role in the brain delivery of opioid analgesic peptides (e.g. deltorphin II) for pain management purposes [143]. Interestingly, Thompson et al. have reported, in rat model of cerebral ischemia, that functional expression of Oatp1a4 is enhanced after hypoxia [144]. Moreover, microvascular expression and activity of Oatp1a4 at the BBB can be further increased through inhibition of TGF-β signaling [144,145]. Since TGF-β1 expression is known to be enhanced after cerebral ischemia [146], pharmacological inhibition of TGF-β pathway could have very critical effect to enhance the function of Oatps influx transporter and ultimately increase CNS drug delivery. Despite showing promising results, care must be taken in the design and evaluation of therapeutics that act through these pathways (Table 2). First, ligand–drug conjugates should have desirable pharmacokinetic properties and maintain drug activity and ligand targeting capability. Second, ligand–drug substrates for one transport system e.g. OATP/Oatp can also transported by at least one additional transporter (e.g. P-gp efflux transporter) and thus, the overall accumulation in the brain may be reduced. Third, the broad nature of many of these transporters and the interference with endogenous substrates can also pose another obstacle toward clinical translation. Likewise, the exact mechanism of BBB permeation of drug-conjugates can be sometimes difficult to predict based on theoretical principles only. For example, attachment of glucose moiety to a peptide can improve the transport across the BBB, but this is not necessarily due to the peptide ability to use the BBB glucose transporter (GLUT1). Finally, ligand–drug conjugates can accumulate in different region of the brain (disease not specific) that may cause undesirable side effect. Moreover, changes in the expression of certain transport systems in the brain in some diseases have critical impact on the translocation ability of ligand–drug conjugates into the brain and perhaps cause heterogenous distribution [42,147].