N -naphthoyl-6 β -naltrexamin

Structural formula
General
Surname	N -naphthoyl-6 β -naltrexamin
other names	17-Cyclopropylmethyl-3,14 β -dihydroxy-4,5α-epoxy-6 β - [(2′-naphthoyl) amido] morphinan ( IUPAC )
Molecular formula	C 31 H 32 N 2 O 4
External identifiers / databases
CAS number 1124167-70-9 Wikidata Q27158094
properties
Molar mass	496.6 g mol −1
Physical state	firmly
Melting point	199–201 ° C (free base)
safety instructions
GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

N - naphthoyl -6 β -naltrexamine (NNTA) is a novel opioid whose structure was designed in connection with the development of highly selective μ-receptor antagonists through molecular modeling . NNTA was originally only used as a reference substance and only shows a low selectivity for the μ-receptor itself.

properties

NNTA selectively activates µ-k opioid receptor heteromers. The substance therefore differs significantly in its spectrum of activity from classic µ-agonists such as morphine , methadone or fentanyl . NNTA is a highly potent agonist - despite the antagonistic structural fragment ( N - cyclopropyl residue) - in cells that express µ- and k-opioid receptors, while it acts as an antagonist in cells that only express µ-receptors such as naltrexone .

The binding of µ-opioid receptors to κ-opioid receptors has a fundamental influence on the binding of ligands and the intracellular biochemical signaling cascades triggered after receptor activation . NNTA has a strong analgesic effect in mice and is 50 times more potent than morphine when administered intravenously, but does not produce any physical opioid dependence in comparison to morphine . Furthermore, NNTA does not lead to self-administration in mice, but rather to an aversion at higher doses (typical for k-agonists). It is therefore assumed that NNTA does not have a euphoric effect in humans, but rather has a dysphoric effect at higher doses and therefore does not induce abuse. It is not yet known whether the dysphoric effect is triggered by μ-k heterodimers , homodimeric k receptors or by other heteromers containing k receptors.

biochemistry

The classic model of G-protein-coupled receptors is based on the assumption that the receptors occur as monomers and that the signal transduction triggered in the cell after the binding of an agonist takes place via monomers. However, since the mid-1970s / early 1980s there have been indications that receptors can form dimers (homomers and heteromers) or oligomers that are also functionally active ( GPCR oligomers ). About 12 different heteromers of opioid receptors are known to date. The heteromerization can influence the binding of exogenous ligands (agonists, antagonists) to the receptor, as well as the coupling of the activated receptor to various intracellular signal proteins ( G proteins , β-arrestins ). This influences the intracellular signal transduction and ultimately the spectrum of action (analgesia, respiratory depression, psychotropic stimulus, physical dependence, etc.) ( functional selectivity , biased agonism ).

Analogues

The amide fragment (structure of the acid residue) significantly influences the binding to the respective receptor and thus the exact biochemical mechanisms of action of similar structures.

An analogue of the NNTA, the N -indolyl-6 β -naltrexamine (INTA) obviously acts as an agonist on µ-κ- and δ-κ-heteromers. It also does not create physical addiction. However, conditioning experiments on animals (conditioned place preference) showed that INTA evidently evokes pleasant psychological effects, while NNTA evokes a more aversive reaction. Based on the results with NNTA, one would expect an aversive reaction in conditioning experiments with INTA if the heteromers act independently of one another. A possible explanation for the different psychotropic effects of INTA compared to NNTA could be higher-order receptor oligomers.

Another structural analogue , N- iodobenzoyl-6 β -naltrexamine (IBNtxA) also has a strong analgesic effect and, according to previous experiments, is not addictive, but differs significantly from NNTA and INTA on a biochemical level. IBNtxA does not work via µ-k heteromers, but apparently via a 6-TM splice variant of the µ-opioid receptor (the main form is the 7-TM protein). In contrast to the 7-TM main form, the 6-TM splice variant apparently requires a partner (possibly β2 adrenoceptors) in order to become functionally active.

Individual evidence

1. ↑ ^{a b c} A. S. Yekkirala, MM Lunzer, CR McCurdy, MD Powers, AE Kalyuzhny, SC Roerig, PS Portoghese: N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of μ / kappa-opioid heteromers. In: Proceedings of the National Academy of Sciences . Volume 108, number 12, March 2011, pp. 5098-5103, doi : 10.1073 / pnas.1016277108 , PMID 21385944 , PMC 3064379 (free full text).
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ↑ Li G., Aschenbach LC, Chen J., Cassidy MP, Stevens DL, Gabra BH, Selley DE, Dewey WL, Westkaemper RB, Zhang Y: Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists. In: J. Med. Chem. Volume 52 , no. 5 , 2009, p. 1416-1427 , PMID 19199782 .
4. ↑ M. Le Naour, MMLunzer, MDPowers, AEKalyuzhny, MABenneyworth, MJThomas, PSPortoghese: Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects. In: J. Med. Chem. Volume 57 , no. 15 , 2014, p. 6383-6392 , PMID 24978316 .
5. ↑ SG Grinnell, S. Majumdar, A. Narayan, V. Le Rouzic, M. Ansonoff, JE Pintar, GW Pasternak: Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA. In: J. Pharmacol. Exp. Ther. tape 350 , no. 3 , 2014, p. 710-718 , PMID 24970924 .
6. ↑ S. Majumdar, S. Grinnell, V. Le Rouzic, M. Burgman, L. Polikar, M. Ansonoff, J. Pintar, YX Pan, GW Pasternak: Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. In: PNAS . tape 108 , no. 49 , 2011, p. 19778-19783 , PMID 22106286 .
7. ^ Z. Lu, J. Xu, GC Rossi, S. Majumdar, GW Pasternak, YX Pan: Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. In: J. Clin. Invest. tape 125 , no. 7 , 2015, p. 2626-2630 , PMID 26011641 .
8. ↑ Samoshkin A, Convertino M, Viet CT, et al .: Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling . In: Scientific Reports . No. 5: 18198 , 2015, doi : 10.1038 / srep18198 , PMC 4676002 (free full text).