Table 1.
GPCR ligands at various stages of preclinical and clinical development
| Target/Category | Name | Mechanism | Preclinical data | Clinical status | References |
|---|---|---|---|---|---|
|
| |||||
| Abuse-deterrent formulations of opioids | MS-Contin OxyContin, etc |
Extended release opioids | Similar to opioid pharmacophores | Clinically used, controversial data suggesting increased misuse of opioids. More studies necessary. | 45,46,49,50 |
|
| |||||
| Peripheral GPCR ligand |
(Cara Tx) CR845 (i.v. and oral) |
Peripherally restricted kappa opioid agonist | Similar to other kappa agonists in rodent pain models (http://www.caratherapeutics.com/files/CARA_CR845_IASP_2008.pdf). Poor CNS penetration (http://www.caratherapeutics.com/cr845-other.shtml) |
Currently under clinical development Ph2a – oral Ph 3 - IV |
95, 278, 279 |
|
| |||||
| Heteromer GPCR ligands |
(Blue Tx) NNTA |
Selective mu- kappa opioid heteromer agonist (initial indication of greater potency and receptor expression in the spinal cord) | Analgesic, no dependence, no CPP | Preclinical IND development | 64 |
| MDAN-21 | Bivalent mu agonist-delta antagonist ligand | Analgesic, no tolerance or CPP Extremely potent analgesic in several rodent models |
No current information on clinical development | 58, 60, 62 | |
| MMG-22 | Bivalent mu agonist-mGluR5 antagonist ligand | Potent analgesia in inflammatory and neuropathic pain models | ND | 63 | |
| MCC-22 | Bivalent mu agonist-CCR5 antagonist ligand | ND | |||
|
| |||||
| Biased GPCR ligands | RB-64 (Trevena) |
Biased KOR ligand | Analgesic, CPA | ND | 72 |
| TRV130 TRV250 TRV734 PZM21 |
Biased mu opioid agonists | Varying levels of analgesic efficacy, no respiratory depression and reduced abuse potential and other side effects | Ph 1 or 2 trials completed, Ph 3 initiated for TRV130 | 84, 280 | |
|
| |||||
| Truncated GPCRs | IBNtxA | 6TM mu opioid truncated receptor. (Site of expression and extent of expression still to be determined) | Analgesic, no CPP | ND | 68–70,281 |
|
| |||||
| AT2R | Mycolactone (Spinifex Pharma) EMA401 |
Ang II R2 blockers (Mechanism still to be determined) | Analgesic, neuralgia indication | Under development for post-herpetic neuralgia. Phase 2 data showed increased efficacy when compared with placebo | 96,98,101 |
|
| |||||
| C5aR |
(Dompé Pharma) DF2593A |
C5aR allosteric antagonist | Allosteric C5aR inhibitor; effective in rodent models of inflammatory and neuropathic pain | ND | 282 |
|
| |||||
| Cannabinoid receptors |
(Various) APD371 LY2828360 S-777469 KHK6188 |
CB1 and 2 inhibitors (spinal and supraspinal mechanisms) | Antinociception, attenuate morphine tolerance | APD371 and KHK6188 in Phase 2 LY2828360 discontinued in phase 2 S-777469 has diverted to atopic dermatitis studies in the clinic |
85,86,283,284 |
|
| |||||
| GPR55 | ML-193 | GPR55 antagonist | Analgesia; agonists are pronociceptive | ND | 285 |
|
| |||||
| α2a-adrenergic receptor | Clonidine Tizanidine Dexmedetomidine |
α2a-adrenergic agonists | Some efficacy in neuropathic pain models in rodents. | Meta-analysis of 28 clinical trials suggests some clinical efficacy | 103–106,108,109 |
|
| |||||
| Chemokine receptors | Morphine + AMD3100 | Opioid+CCR antagonist | Reduced OIH and opioid tolerance in rodents, reduced neuropathic pain | ND | 121,132 |
| AZD2423 | CCR2 antagonist | Failed clinical trial | 133 | ||
| RAP-103 | Mixed CCR2- CCR5 antagonist | Attenuates neuropathic pain | ND | 134 | |
Key: ND – No data on clinical development, CPP – Conditioned Place Preference, CPA – Conditioned Place Aversion