- Email: [email protected]
Biased Opioid Receptor Ligands: Gain without Pain
TEM 1209 No. of Pages 3
Spotlight
therapeutics with potentially reduced adverse effects [3,4]. Although the concept of biased agonism and the potential for developing novel therapeutics has been around for several years, there are still only a handful of examples in animal models that directly support the 1 Ravi Ranjan, therapeutic promise of biased ligands. Shubhi Pandey,1 and Brust et al. now provide direct evidence Arun K. Shukla1,* in animal models that, unlike balanced (or unbiased) k-OR agonists, a G proKappa opioid receptor (k-OR) ago- tein-biased k-OR ligand does not elicit nists are promising therapeutic the adverse effects of sedation and dyscandidates for pain and itch; how- phoria [5] (Figure 1).
Biased Opioid Receptor Ligands: Gain without Pain
ever, they also exhibit the adverse effects of sedation and dysphoria. A recent study has demonstrated that a G protein-biased agonist for k-OR provides effective pain and itch relief without causing sedation or dysphoria, in animal models. The central role of G-protein-coupled receptors (GPCRs, also known as seven transmembrane receptors) in almost every aspect of human physiology makes them the largest class of drug targets for treating a range of human disorders [1]. Some of the GPCR-targeted drugs include angiotensin receptor blockers (ARBs) for hypertension, histamine receptor antagonists for allergy, beta-adrenergic agonists for asthma, and opioid receptor agonists as analgesics. In many cases, the adverse effects associated with GPCR-targeted drugs present a significant nuance, and compromise their therapeutic utility. The recent discovery of a mostly generic GPCR signaling paradigm where activated receptors can signal through parallel and independent signaling pathways mediated by G proteins and b-Arrestins (barrs) offers new hope to change this scenario [2]. The observation that these independent signaling mechanisms can be linked to distinct physiological outcomes, and can be pharmacologically separated by using biased GPCR ligands, opens a promising avenue for designing GPCR-targeted
k-OR is a prototypical GPCR that belongs to the rhodopsin-like subfamily of opioid receptors. Activation of k-OR, similar to other members of this subfamily (m-OR and d-OR), by classical agonists promotes antinociceptive effects and, therefore, represents a target for designing potent analgesics. In addition, k-OR agonists also efficiently suppress nonhistamine-related itch, referred to as pruritis, resulting in the development of an orally active potent k-OR agonist, nalfurafine, which is currently in use for the treatment of pruritis in Japan. Unfortunately, however, k-OR agonists also exhibit symptoms of dysphoria and sedation, because they decrease the extracellular concentration of dopamine in dopaminergic nerve terminals, although a clear mechanism remains to be established. This has been one of the bottlenecks that have limited the more aggressive clinical development of k-OR agonists as analgesics. The discoveries that k-OR, similar to other GPCRs, also has a barr-dependent signaling component, and that dysphoria symptoms upon k-OR activation are linked to barr-dependent p38 MAP kinase activation, suggest that G protein-biased k-OR agonists [103_TD$IF]might display antinociceptive properties without eliciting dysphoriarelated behaviors [6]. The compound referred to as triazole 1.1 and used by Brust et al., exhibited preferential coupling and activation of Gai protein over barrs
compared with a reference k-OR agonist, U50,488H, when tested in cellular and in vitro set-ups [5,7]. As expected, the antinociceptive properties of Triazole 1.1 were essentially comparable to those of U50,488H in mouse models, as assessed by a standard tail-flick assay, which measures the withdrawal time when a small portion of the tail is immersed in warm water. Furthermore, Triazole 1.1 was also able to effectively suppress itch in mice, evaluated by measuring the number of scratching bouts in mice injected with chloroquine phosphate subcutaneously as a readout of itching. Although slightly less potent than the reference unbiased k-OR agonist, the overall antinociceptive and itch suppression efficacy of Triazole 1.1 was comparable, suggesting that substantial reduction of barr coupling does not compromise the beneficial effects mediated through Gai signaling upon k-OR activation. As mentioned above, the adverse effects of dysphoria and sedation are generally attributed, at least in part, to the ability of k-OR agonists to decrease the extracellular dopamine concentration in dopaminergic nerve terminals. As expected, at equianalgesic dosage, U50,488H significantly reduced the locomotor activity of mice in a dose-dependent fashion, whereas Triazole 1.1 did not alter the locomotor response significantly. Interestingly, this lack of a sedation-like effect of Triazole 1.1 appeared to arise from its inability to decrease the dopamine release in mouse striatum, thus not adversely affecting the dopaminergic transmission. Furthermore, in a rat model of intracranial self-stimulation (ICSS), which measures the ability of a drug to influence the reward circuit in the brain, Triazole 1.1 did not trigger signs of dysphoria and aversion, unlike a typical k-OR agonist. These results directly establish the ability of Triazole 1.1 to physiologically segregate the nociception and itch suppression from sedative and dysphoric symptoms, by preferentially engaging Gai over barrs to activated k-OR. Although the
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
1
TEM 1209 No. of Pages 3
Balanced (unbiased) agonist (U50,488H) Cl
Cl
Gαi-biased agonist (Triazole 1.1 ) O
O H3C
N
CH3
F3C
K-OR
N
K-OR
N
N
S
N
N
Gαi
βarr
Gαi
βarr
Analgesia ltch suppression
Sedaon Dysphoria
Analgesia Itch suppression
Sedaon Dysphoria
Figure 1. A Biased Kappa Opioid Receptor (k-OR) Ligand Offers Promising Therapeutic Intervention for Pain and Itch without Eliciting the Adverse Effects of Sedation and Dysphoria. A balanced (or unbiased) k-OR agonist U50,488H elicited both G protein and b-Arrestin (barr) coupling and activation. As a result, although it effectively suppresses pain and itch sensations through the G protein-dependent signaling pathway, it also results in dysphoria and sedation, potentially through barr-dependent signaling cascades. Brust et al. recently reported the discovery that a G protein-biased k-OR agonist, referred to as Triazole 1.1, preferentially engaged and activated Gai protein over barr. In mouse and rat models, Triazole 1.1 maintained analgesic and itch suppression activities, but did not lead to sedative and dysphoric responses. These results not only strengthen the notion that the physiological outcomes downstream of G protein and barr can be pharmacologically segregated in vivo, but also offer a potential solution to the longstanding challenge of designing k-OR-targeting analgesics without common adverse effects.
Phase 3 clinical trial for managing moderate-to-severe acute pain. Analogous to Triazole 1.1, TRV130 also exhibits preferential coupling and activation of Gai over barrs [8]. Compared with morphine, a clinically used m-OR-balanced agonist and potent analgesic, TRV130 displays significantly attenuated adverse effects, such as respiratory depression and gasA Gai-biased ligand of the m-OR, TRV130 trointestinal dysfunction, in animal mod(oliceridine), developed by Trevena, is in a els, while maintaining the desired molecular mechanism by which Triazole 1.1 induces physiological outcomes remains to be established, the current study provides a robust drive to move forward with further optimization and testing of Triazole-based scaffolds, in-depth pharmacokinetic studies, and, hopefully, subsequent clinical trials.
2
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
analgesic effects similar to those of morphine [8]. Furthermore, another recent study described the structure-based discovery of a Gai-biased m-OR ligand, referred to as PZM21, which showed initial promise in animal studies as a potent analgesic without respiratory depression and morphine-like reinforcing effects [9]. Interestingly, the discovery of PZM21 using a virtual docking approach with the crystal structure of m-OR as a
TEM 1209 No. of Pages 3
template represents the first example of the structure-based discovery of a biased GPCR ligand [9]. Going forward, emerging structural and mechanistic insights into receptor–effector interactions and their implications for regulating functional outcomes is likely to further fine-tune the ongoing efforts to design biased GPCR ligands [10].
3. Violin, J.D. et al. (2014) Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35, 308–316
Acknowledgments
5. Brust, T.F. et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci. Signal. 9, ra117
The research program in A.K.S.’s laboratory is currently supported by an Intermediate Fellowship from
Taken together with other recent studies describing the in vivo potential of biased ligands, the study by Brust et al. further strengthens the notion that biased GPCR ligands have significant promise to dissociate physiological outcomes downstream of activated GPCRs, thereby offering better therapeutic possibilities [5]. Despite a minor set-back in Phase 2b clinical trials with TRV027, a barrbiased angiotensin receptor agonist as
2. Shukla, A.K. et al. (2011) Emerging paradigms of betaarrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36, 457–469
a potential therapeutic agent in congestive heart failure, this area of biased GPCR agonists is likely to offer rewarding outcomes, especially with more intensive and focused efforts from the pharmaceutical industry.
the Wellcome Trust DBT India Alliance (IA/I/14/1/ 501285), Department of Science and Technology (DST), and the Council of Scientific and Industrial Research (CSIR). 1
Department of Biological Sciences and Bioengineering,
Indian Institute of Technology, Kanpur 208016, India *Correspondence: [email protected] (A.K. Shukla). http://dx.doi.org/10.1016/j.tem.2017.01.001 References 1. Jacobson, K.A. (2015) New paradigms in GPCR drug discovery. Biochem. Pharmacol. 98, 541–555
4. Kumari, P. et al. (2015) Emerging approaches to GPCR ligand screening for drug discovery. Trends Mol. Med. 21, 687–701
6. Bruchas, M.R. et al. (2007) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J. Neurosci. 27, 11614–11623 7. Zhou, L. et al. (2013) Development of functionally selective, small molecule agonists at kappa opioid receptors. J. Biol. Chem. 288, 36703–36716 8. DeWire, S.M. et al. (2013) A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708–717 9. Manglik, A. et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 10. Kumari, P. et al. (2016) Functional competence of a partially engaged GPCR-beta-arrestin complex. Nat. Commun. 7, 13416
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
3
Spotlight
therapeutics with potentially reduced adverse effects [3,4]. Although the concept of biased agonism and the potential for developing novel therapeutics has been around for several years, there are still only a handful of examples in animal models that directly support the 1 Ravi Ranjan, therapeutic promise of biased ligands. Shubhi Pandey,1 and Brust et al. now provide direct evidence Arun K. Shukla1,* in animal models that, unlike balanced (or unbiased) k-OR agonists, a G proKappa opioid receptor (k-OR) ago- tein-biased k-OR ligand does not elicit nists are promising therapeutic the adverse effects of sedation and dyscandidates for pain and itch; how- phoria [5] (Figure 1).
Biased Opioid Receptor Ligands: Gain without Pain
ever, they also exhibit the adverse effects of sedation and dysphoria. A recent study has demonstrated that a G protein-biased agonist for k-OR provides effective pain and itch relief without causing sedation or dysphoria, in animal models. The central role of G-protein-coupled receptors (GPCRs, also known as seven transmembrane receptors) in almost every aspect of human physiology makes them the largest class of drug targets for treating a range of human disorders [1]. Some of the GPCR-targeted drugs include angiotensin receptor blockers (ARBs) for hypertension, histamine receptor antagonists for allergy, beta-adrenergic agonists for asthma, and opioid receptor agonists as analgesics. In many cases, the adverse effects associated with GPCR-targeted drugs present a significant nuance, and compromise their therapeutic utility. The recent discovery of a mostly generic GPCR signaling paradigm where activated receptors can signal through parallel and independent signaling pathways mediated by G proteins and b-Arrestins (barrs) offers new hope to change this scenario [2]. The observation that these independent signaling mechanisms can be linked to distinct physiological outcomes, and can be pharmacologically separated by using biased GPCR ligands, opens a promising avenue for designing GPCR-targeted
k-OR is a prototypical GPCR that belongs to the rhodopsin-like subfamily of opioid receptors. Activation of k-OR, similar to other members of this subfamily (m-OR and d-OR), by classical agonists promotes antinociceptive effects and, therefore, represents a target for designing potent analgesics. In addition, k-OR agonists also efficiently suppress nonhistamine-related itch, referred to as pruritis, resulting in the development of an orally active potent k-OR agonist, nalfurafine, which is currently in use for the treatment of pruritis in Japan. Unfortunately, however, k-OR agonists also exhibit symptoms of dysphoria and sedation, because they decrease the extracellular concentration of dopamine in dopaminergic nerve terminals, although a clear mechanism remains to be established. This has been one of the bottlenecks that have limited the more aggressive clinical development of k-OR agonists as analgesics. The discoveries that k-OR, similar to other GPCRs, also has a barr-dependent signaling component, and that dysphoria symptoms upon k-OR activation are linked to barr-dependent p38 MAP kinase activation, suggest that G protein-biased k-OR agonists [103_TD$IF]might display antinociceptive properties without eliciting dysphoriarelated behaviors [6]. The compound referred to as triazole 1.1 and used by Brust et al., exhibited preferential coupling and activation of Gai protein over barrs
compared with a reference k-OR agonist, U50,488H, when tested in cellular and in vitro set-ups [5,7]. As expected, the antinociceptive properties of Triazole 1.1 were essentially comparable to those of U50,488H in mouse models, as assessed by a standard tail-flick assay, which measures the withdrawal time when a small portion of the tail is immersed in warm water. Furthermore, Triazole 1.1 was also able to effectively suppress itch in mice, evaluated by measuring the number of scratching bouts in mice injected with chloroquine phosphate subcutaneously as a readout of itching. Although slightly less potent than the reference unbiased k-OR agonist, the overall antinociceptive and itch suppression efficacy of Triazole 1.1 was comparable, suggesting that substantial reduction of barr coupling does not compromise the beneficial effects mediated through Gai signaling upon k-OR activation. As mentioned above, the adverse effects of dysphoria and sedation are generally attributed, at least in part, to the ability of k-OR agonists to decrease the extracellular dopamine concentration in dopaminergic nerve terminals. As expected, at equianalgesic dosage, U50,488H significantly reduced the locomotor activity of mice in a dose-dependent fashion, whereas Triazole 1.1 did not alter the locomotor response significantly. Interestingly, this lack of a sedation-like effect of Triazole 1.1 appeared to arise from its inability to decrease the dopamine release in mouse striatum, thus not adversely affecting the dopaminergic transmission. Furthermore, in a rat model of intracranial self-stimulation (ICSS), which measures the ability of a drug to influence the reward circuit in the brain, Triazole 1.1 did not trigger signs of dysphoria and aversion, unlike a typical k-OR agonist. These results directly establish the ability of Triazole 1.1 to physiologically segregate the nociception and itch suppression from sedative and dysphoric symptoms, by preferentially engaging Gai over barrs to activated k-OR. Although the
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
1
TEM 1209 No. of Pages 3
Balanced (unbiased) agonist (U50,488H) Cl
Cl
Gαi-biased agonist (Triazole 1.1 ) O
O H3C
N
CH3
F3C
K-OR
N
K-OR
N
N
S
N
N
Gαi
βarr
Gαi
βarr
Analgesia ltch suppression
Sedaon Dysphoria
Analgesia Itch suppression
Sedaon Dysphoria
Figure 1. A Biased Kappa Opioid Receptor (k-OR) Ligand Offers Promising Therapeutic Intervention for Pain and Itch without Eliciting the Adverse Effects of Sedation and Dysphoria. A balanced (or unbiased) k-OR agonist U50,488H elicited both G protein and b-Arrestin (barr) coupling and activation. As a result, although it effectively suppresses pain and itch sensations through the G protein-dependent signaling pathway, it also results in dysphoria and sedation, potentially through barr-dependent signaling cascades. Brust et al. recently reported the discovery that a G protein-biased k-OR agonist, referred to as Triazole 1.1, preferentially engaged and activated Gai protein over barr. In mouse and rat models, Triazole 1.1 maintained analgesic and itch suppression activities, but did not lead to sedative and dysphoric responses. These results not only strengthen the notion that the physiological outcomes downstream of G protein and barr can be pharmacologically segregated in vivo, but also offer a potential solution to the longstanding challenge of designing k-OR-targeting analgesics without common adverse effects.
Phase 3 clinical trial for managing moderate-to-severe acute pain. Analogous to Triazole 1.1, TRV130 also exhibits preferential coupling and activation of Gai over barrs [8]. Compared with morphine, a clinically used m-OR-balanced agonist and potent analgesic, TRV130 displays significantly attenuated adverse effects, such as respiratory depression and gasA Gai-biased ligand of the m-OR, TRV130 trointestinal dysfunction, in animal mod(oliceridine), developed by Trevena, is in a els, while maintaining the desired molecular mechanism by which Triazole 1.1 induces physiological outcomes remains to be established, the current study provides a robust drive to move forward with further optimization and testing of Triazole-based scaffolds, in-depth pharmacokinetic studies, and, hopefully, subsequent clinical trials.
2
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
analgesic effects similar to those of morphine [8]. Furthermore, another recent study described the structure-based discovery of a Gai-biased m-OR ligand, referred to as PZM21, which showed initial promise in animal studies as a potent analgesic without respiratory depression and morphine-like reinforcing effects [9]. Interestingly, the discovery of PZM21 using a virtual docking approach with the crystal structure of m-OR as a
TEM 1209 No. of Pages 3
template represents the first example of the structure-based discovery of a biased GPCR ligand [9]. Going forward, emerging structural and mechanistic insights into receptor–effector interactions and their implications for regulating functional outcomes is likely to further fine-tune the ongoing efforts to design biased GPCR ligands [10].
3. Violin, J.D. et al. (2014) Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35, 308–316
Acknowledgments
5. Brust, T.F. et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci. Signal. 9, ra117
The research program in A.K.S.’s laboratory is currently supported by an Intermediate Fellowship from
Taken together with other recent studies describing the in vivo potential of biased ligands, the study by Brust et al. further strengthens the notion that biased GPCR ligands have significant promise to dissociate physiological outcomes downstream of activated GPCRs, thereby offering better therapeutic possibilities [5]. Despite a minor set-back in Phase 2b clinical trials with TRV027, a barrbiased angiotensin receptor agonist as
2. Shukla, A.K. et al. (2011) Emerging paradigms of betaarrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36, 457–469
a potential therapeutic agent in congestive heart failure, this area of biased GPCR agonists is likely to offer rewarding outcomes, especially with more intensive and focused efforts from the pharmaceutical industry.
the Wellcome Trust DBT India Alliance (IA/I/14/1/ 501285), Department of Science and Technology (DST), and the Council of Scientific and Industrial Research (CSIR). 1
Department of Biological Sciences and Bioengineering,
Indian Institute of Technology, Kanpur 208016, India *Correspondence: [email protected] (A.K. Shukla). http://dx.doi.org/10.1016/j.tem.2017.01.001 References 1. Jacobson, K.A. (2015) New paradigms in GPCR drug discovery. Biochem. Pharmacol. 98, 541–555
4. Kumari, P. et al. (2015) Emerging approaches to GPCR ligand screening for drug discovery. Trends Mol. Med. 21, 687–701
6. Bruchas, M.R. et al. (2007) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J. Neurosci. 27, 11614–11623 7. Zhou, L. et al. (2013) Development of functionally selective, small molecule agonists at kappa opioid receptors. J. Biol. Chem. 288, 36703–36716 8. DeWire, S.M. et al. (2013) A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708–717 9. Manglik, A. et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 10. Kumari, P. et al. (2016) Functional competence of a partially engaged GPCR-beta-arrestin complex. Nat. Commun. 7, 13416
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy
3