Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • Our overall goal is to

    2021-10-23

    Our overall goal is to develop selective compounds for low-affinity/high-capacity transporters inhibitors (i.e. OCT1–3 and PMAT), and provide the field with much needed, specific pharmacological tools to study these transporters. In our initial efforts, we synthesized halogen substituted analogs and cyanine analogs of D22 yielding compounds that had greater affinity at hOCT3 rather than hOCT2 and hPMAT, however, none with improved selectivity for OCT3 over D22. Several compounds also had modest affinity for high-affinity/low-capacity monoamine transporters, SERT in particular, which may contribute to their “stand-alone” antidepressant-like effects we previously reported (Krause-Heuer et al., 2017). For example, Piperlongumine synthesis 6, which produced the most robust antidepressant-like effect (Krause-Heuer et al., 2017), had the greatest affinity for SERT (0.75 µM), combined with affinity for OCT3 equivalent to corticosterone (0.77 µM). This contrasts to D22 with affinity values of 26.2 µM and 0.2 µM at SERT and OCT3, respectively. Thus, a possible reason for a lack of antidepressant-like effect of D22 on its own, in the absence of an SSRI (Horton et al., 2013), is its relatively low affinity for SERT, thereby supporting our contention that combined SERT/OCT3 pharmacotherapeutics may have improved efficacy for treating depression, and related serotonin-linked pathologies. The concept of targeting multiple transporters to achieve greater concentrations of extracellular monoamines is not new. However, tactics have largely focused on combined blockade of DAT, NET, SERT, monoamine receptors, and/or metabolism inhibitors (Moret, 2005, Sambunaris et al., 1997). Current selective reuptake inhibitors for the high-affinity/low-capacity transporters (SERT, NET, DAT) have no appreciable activity at OCT2, OCT3, and PMAT (Emberger et al., 2011, Haenisch and Bönisch, 2010, Matthaeus et al., 2015, Wang et al., 2014, Zhou et al., 2007). Work by us and others support the idea for greater therapeutic potential by blockade of the low-affinity/high-capacity transporter system, in tandem with blockers of high-affinity/low capacity transporters, especially in instances of resistance to high-affinity monoamine transporter therapies (Daws et al., 2013, Hagan et al., 2011, Horton et al., 2013). Our comparative analysis of this small library of D22 analogs identified select compounds that, unlike parent D22, lack activity at alpha-1 adrenoceptors, have independent antidepressant-like effects, and reduced potency to suppress spontaneous locomotion (Krause-Heuer et al., 2017). The present study extends these findings to show that most analogs have significant binding preference for hOCT3 versus hOCT2 or hPMAT. Moreover, compounds 4, 6 and 7 show potential as drugs with selective action at the low-affinity transport system (OCT3), but also SERT and/or DAT binding ability. Unlike D22, select D22 analogs were bimodal inhibitors of high-affinity transporters determined by their binding affinity at SERT and DAT. Since combination inhibitors can often be more efficacious than monotherapies (Moret, 2005), this study supports the notion that the pharmacological method of dual blockade of both the low-affinity/high-capacity and high-affinity/low-capacity transporter families can be of future value. Development of drugs with low- and high-affinity transporter blockade activity in a single compound warrants further investigation towards discovering improved treatments for disorders sub-optimally managed by currently available medications.
    Acknowledgements We gratefully acknowledge the Australian Institute of Nuclear Science and Engineering for the provision of a 2017 postgraduate research award to Jeremy Dobrowolski.
    Introduction The ultimate goal of designing drug delivery systems is to achieve better therapeutic outcomes with lower side effects. Current approaches include improving the physicochemical properties of formulations and/or addressing the complex fates of drugs following in vivo delivery1., 2., 3., 4., 5., 6.. With the rapid developments in nanotechnology and carrier materials, nanoparticulate drug delivery systems (nano-DDS) show great progress in drug delivery over the past few decades3., 4., 5., 6., 7., 8., 9.. Drug molecules encapsulated in nanocarriers usually demonstrate totally different delivery characteristics instead of their intrinsic properties, due to the shielding effect of nano-DDS8., 10.. This permits development of more versatile drug delivery strategies as compared with only changing the physicochemical properties of compounds. Therefore, rationally designing various nanocarriers and making specific modifications on the nano-DDS can achieve more effective drug delivery.