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PF-06655075

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PF-06655075
Clinical data
Other namesPF06655075; PF-6655075; PF6655075
Drug classOxytocin receptor agonist; Vasopressin V1A receptor antagonist; Vasopressin V2 receptor agonist
ATC code
  • None
Identifiers
  • (4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-N-[2-[[(2S)-1-[(2-amino-2-oxoethyl)amino]-6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(hexadecanoylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-1-oxohexan-2-yl]amino]-2-oxoethyl]-10-(3-amino-3-oxopropyl)-13-[(2S)-butan-2-yl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC75H130N14O22S2
Molar mass1644.06 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)NCCCC[C@@H](C(=O)NCC(=O)N)NC(=O)CNC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CC(=O)N)CCC(=O)N)[C@@H](C)CC)CC2=CC=C(C=C2)O)N
  • InChI=1S/C75H130N14O22S2/c1-4-6-7-8-9-10-11-12-13-14-15-16-17-21-65(94)81-30-32-105-34-36-107-38-40-109-42-44-111-46-45-110-43-41-108-39-37-106-35-33-104-31-28-66(95)80-29-19-18-20-57(70(98)82-49-64(79)93)84-67(96)50-83-71(99)61-52-113-112-51-56(76)69(97)86-59(47-54-22-24-55(90)25-23-54)74(102)89-68(53(3)5-2)75(103)85-58(26-27-62(77)91)72(100)87-60(48-63(78)92)73(101)88-61/h22-25,53,56-61,68,90H,4-21,26-52,76H2,1-3H3,(H2,77,91)(H2,78,92)(H2,79,93)(H,80,95)(H,81,94)(H,82,98)(H,83,99)(H,84,96)(H,85,103)(H,86,97)(H,87,100)(H,88,101)(H,89,102)/t53-,56-,57-,58-,59-,60-,61-,68-/m0/s1
  • Key:NRZDYVUJLXPBEW-PIFLIQEJSA-N

PF-06655075, also known as PF1 or as ASK1476, is a peripherally selective long-acting peptide oxytocin receptor agonist which is used in scientific research.[1][2][3] It is a lipidated analogue of oxytocin with dramatically enhanced metabolic stability and increased oxytocin receptor selectivity.[1][4][5]

PF-06655075 is a highly potent near-full agonist of the oxytocin receptor with similar affinity and potency as oxytocin itself (Ki = 0.037 nM; EC50Tooltip half-maximal effective concentration = 0.025 nM; EmaxTooltip maximal efficacy = 90%) and to a much lesser extent is an antagonist of the vasopressin V1A receptor (Ki = 4.37 nM; EC50 = >1,000 nM).[1][3] It is also a potent agonist of the vasopressin V2 receptor (EC50 = 0.36 nM), with about 14-fold lower activational potency than at the oxytocin receptor.[3] The drug has been found to inhibit conditioned fear-induced freezing behavior and anxiety in rodents when given either centrally or peripherally.[1][4][5] It has been found to decrease alcohol consumption when given centrally but not peripherally in rodents.[2][6][7][8] In addition, PF-06655075 robustly reduced food intake and body weight when given peripherally in rodents similarly to oxytocin but with less frequent and more convenient administration.[1]

Whereas oxytocin itself has an extremely short plasma elimination half-life, for instance 2 to 4 minutes in humans and 7 minutes in rats, PF-06655075 showed had a half-life of 8.5 hours by intravenous injection in rats.[1] Non-depot subcutaneous injection resulted in an oxytocin half-life of 0.5 hours and a PF-06655075 half-life of 3.2 hours, whereas depot subcutaneous injection gave an oxytocin half-life of 7.3 hours and a PF-06655075 half-life of 309 hours.[1] Both oxytocin and PF-06655075 are highly peripherally selective, with oxytocin showing a brain-to-plasma ratio of approximately 1% and PF-06655075 showing a ratio of about 2%.[1] Unlike oxytocin, which is not highly bound to plasma proteins, PF-06655075 shows high plasma protein binding, and this is involved in its resistance to metabolism and longer duration.[1]

The chemical synthesis of PF-06655075 has been described.[1] An analogue of PF-06655075, PF-06478939 (PF2), has also been described.[1]

PF-06655075 was developed by Pfizer for use as a tool in scientific research and was first described in the scientific literature by 2016.[1]

See also

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References

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  1. 1 2 3 4 5 6 7 8 9 10 11 12 Modi ME, Majchrzak MJ, Fonseca KR, Doran A, Osgood S, Vanase-Frawley M, Feyfant E, McInnes H, Darvari R, Buhl DL, Kablaoui NM (August 2016). "Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing". J Pharmacol Exp Ther. 358 (2): 164–172. doi:10.1124/jpet.116.232702. PMC 4959095. PMID 27217590.
  2. 1 2 Tunstall BJ, Kirson D, Zallar LJ, McConnell SA, Vendruscolo JC, Ho CP, Oleata CS, Khom S, Manning M, Lee MR, Leggio L, Koob GF, Roberto M, Vendruscolo LF (April 2019). "Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala". PLOS Biol. 17 (4) e2006421. doi:10.1371/journal.pbio.2006421. PMC 6467366. PMID 30990816.
  3. 1 2 3 Elfers CT, Blevins JE, Lawson EA, Pittner R, Silva D, Kiselyov A, Roth CL (2021). "Robust Reductions of Body Weight and Food Intake by an Oxytocin Analog in Rats". Front Physiol. 12 726411. doi:10.3389/fphys.2021.726411. PMC 8502973. PMID 34646154.
  4. 1 2 Pflimlin E, Zhou Z, Amso Z, Fu Q, Lee C, Muppiddi A, Joseph SB, Nguyen-Tran V, Shen W (January 2020). "Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects". J Med Chem. 63 (1): 382–390. doi:10.1021/acs.jmedchem.9b01862. PMID 31850759. Recently, a long-acting OTR agonist named PF-06655075, containing a poly(ethylene glycol) (PEG) spacer and a palmitoyl group conjugated to Lys(8) of the peptide sequence, was shown to have an extended half-life (around 20 h) with efficacy in modulating fear in a rodent model of anxiety.32
  5. 1 2 Cid-Jofré V, Moreno M, Reyes-Parada M, Renard GM (November 2021). "Role of Oxytocin and Vasopressin in Neuropsychiatric Disorders: Therapeutic Potential of Agonists and Antagonists". Int J Mol Sci. 22 (21) 12077. doi:10.3390/ijms222112077. PMC 8584779. PMID 34769501. Another agonist with interesting characteristics is PF-06655075 (PFI). This is a non-brain-penetrant peptide with increased selectivity for the OT-R. In 2016, Modi et al. [170] showed that both central and peripheral administration of PFI inhibited freezing in response to a conditioned stimulus using the conditioned fear paradigm. Interestingly, it was shown that peripheral PFI administration resulted in a sustained level in plasma concentration for more than 20 h, but did not induce a detectable level at the brain tissue level. As a result, the authors suggest that exposure to plasma or cerebrospinal fluid might be sufficient to evoke the described behavioral effects.
  6. ↑ Roberto M, Kirson D, Khom S (February 2021). "The Role of the Central Amygdala in Alcohol Dependence". Cold Spring Harb Perspect Med. 11 (2) a039339. doi:10.1101/cshperspect.a039339. PMC 7382982. PMID 31988201. In collaboration with researchers at the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse, we found that intracerebroventricular oxytocin or the non–blood barrier penetrant OXTR agonist PF-06655075 blocked the enhanced motivation and escalated alcohol drinking seen in dependent rats. In addition, peripheral administration of PF-06655075 did not decrease drinking and systemic administration of the peripherally restricted OXTR antagonist L-371,257 did not block the effects of centrally administered oxytocin (Tunstall et al. 2019). These results suggest oxytocin acts in the brain to decrease excessive alcohol drinking seen with alcohol dependence.
  7. ↑ Wronikowska-Denysiuk O, Mrozek W, Budzyńska B (February 2023). "The Role of Oxytocin and Vasopressin in Drug-Induced Reward-Implications for Social and Non-Social Factors". Biomolecules. 13 (3): 405. doi:10.3390/biom13030405. PMC 10046619. PMID 36979340.
  8. ↑ Esmaili-Shahzade-Ali-Akbari P, Bozorgnia A, Shaterian M, Jandaghian S, Moghimi Shahri S (July 2025). "Oxytocin Neuropeptide in the Control of Drug Dependence: A Review of Past Studies and Future Challenges". Eur J Neurosci. 62 (1) e70197. doi:10.1111/ejn.70197. PMID 40639928.
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