Biology subjects

Bohn, L. M.

Publications and source records attributed to Bohn, L. M..

4 recordsLinked to original sources

bioRxiv2025

Triazole 187 is a biased KOR agonist that suppresses itch without sedation and induces anxiolytic-like behaviors in mice.

Kappa opioid receptor agonists are clinically used to treat pruritis and have therapeutic potential for the treatment of pain and neuropsychiatric disorders. We have previously shown that triazole 1.1 is a G protein signaling-biased KOR agonist, that can suppress itch without producing signs of sedation in mice. This profile was recapitulated in rats and non-human primates however, triazole 1.1 had limited potency as an antipruritic. Here we describe a more potent, G protein signaling-biased agonist, triazole 187. Triazole 187 is a potent antipruritic agent and does not decrease spontaneous locomotor activity; interestingly, it produces anxiolytic-like behaviors in mice, an effect not observed for triazole 1.1. In addition to curbing sedation, triazole 187 produces only mild diuresis, resulting in 30% of urine output induced by U50,488H at dose that is 188-fold the antipruritic potency dose. Compounds like triazole 187 may present a means to treat anxiety accompanied by persistent chronic itch while avoiding sedation and diuresis accompanied by typical KOR agonists. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/638680v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17e9e6aorg.highwire.dtl.DTLVardef@1d27741org.highwire.dtl.DTLVardef@9389dcorg.highwire.dtl.DTLVardef@3fd825_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG

pharmacology and toxicology↗

bioRxiv2023

Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine

Opioid analgesics like morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Here we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35S-GTP{gamma}S binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists, SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.

pharmacology and toxicology↗

bioRxiv2020

Re-evaluating how low intrinsic efficacy and apparent bias for G protein activation relates to the improved side effect profiles of new opioid agonists

In a recent report in Science Signaling (DOI: 10.1126/scisignal.aaz3140), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although many of the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that since they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor (GPCR) response in a system, while biased agonism takes into consideration not only intrinsic efficacy, but also potency of an agonist in an assay. Herein, we have re-analyzed the data presented in the published work (DOI: 10.1126/scisignal.aaz3140) (including the recent Erratum: DOI: 10.1126/scisignal.abf9803) to derive intrinsic efficacy and bias factors as {Delta}{Delta}log({tau}/KA) and {Delta}{Delta}log(Emax/EC50). Based on this reanalysis, the data support the conclusion that biased agonism, favoring G protein signaling, was observed. Moreover, a conservation of rank order intrinsic efficacy was not observed upon comparing responses in each assay, further suggesting that multiple active receptor states were present. These observations agree with prior studies wherein oliceridine, PZM21 and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, the data in the Science Signaling manuscript does provide strong corroborating evidence that G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.

pharmacology and toxicology↗

bioRxiv2020

Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain.

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTP{gamma}S binding over {beta}arrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTP{gamma}S binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.

pharmacology and toxicology↗