SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist

E. J. Bilsky, S. N. Calderon, T. Wang, R. N. Bernstein, P. Davis, Victor J Hruby, R. W. McNutt, R. B. Rothman, K. C. Rice, Frank Porreca

Research output: Contribution to journalArticle

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Abstract

The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective δ agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The δ selective antagonist ICI 174,864 (1 μM) and the μ selective antagonist CTAP (1 μM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (δ receptors) rather than against those labeled by [3H]DAMGO (μ receptors) or [3H]U69, 593 κ receptors) in mouse whole-brain assays. The ratios of the calculated K(i) values for SNC 80 at μ/δ and κ/δ sites were 495- and 248- fold, respectively, which indicates a significant degree of δ selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95% C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95% C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SNC 80 antinociception was antagonized by pretreatment with i.c.v. naloxone (3 nmol), with i.c.v. or i.th. N,N-diallyl- Tyr-(Aib)2-Phe-Leu-OH(Aib=α-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindole (20 mg/kg), but not i.c.v. or i.th. β-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagonized by i.c.v. pretreatment with either [D-Ala2,Leu5,Cys6]enkephalin (a putative δ1 antagonist) or [D-Ala2, Cys4]deltorphin (a putative δ2 antagonist), but not by β-funaltrexamine (a μ antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid δ1 and δ2, but not μ, receptors. On the basis of its profile in vivo and in vitro, SNC 80 is perhaps the first highly selective, nonpeptidic and systemically active opioid δ agonist. SNC 80 promises to be a useful compound for the exploration of opioid δ-receptor pharmacology and provides a basis for the further identification of selective nonpeptidic δ ligands.

Original languageEnglish (US)
Pages (from-to)359-366
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume273
Issue number1
StatePublished - 1995

Fingerprint

Opioid Analgesics
naltrindole
Vas Deferens
4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
Inhibitory Concentration 50
Pharmacology
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Ligands
Radioligand Assay
Enkephalins
Opioid Receptors
Naloxone
Ileum
Tail
Guinea Pigs

ASJC Scopus subject areas

  • Pharmacology

Cite this

SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist. / Bilsky, E. J.; Calderon, S. N.; Wang, T.; Bernstein, R. N.; Davis, P.; Hruby, Victor J; McNutt, R. W.; Rothman, R. B.; Rice, K. C.; Porreca, Frank.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 273, No. 1, 1995, p. 359-366.

Research output: Contribution to journalArticle

Bilsky, EJ, Calderon, SN, Wang, T, Bernstein, RN, Davis, P, Hruby, VJ, McNutt, RW, Rothman, RB, Rice, KC & Porreca, F 1995, 'SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist', Journal of Pharmacology and Experimental Therapeutics, vol. 273, no. 1, pp. 359-366.
Bilsky, E. J. ; Calderon, S. N. ; Wang, T. ; Bernstein, R. N. ; Davis, P. ; Hruby, Victor J ; McNutt, R. W. ; Rothman, R. B. ; Rice, K. C. ; Porreca, Frank. / SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist. In: Journal of Pharmacology and Experimental Therapeutics. 1995 ; Vol. 273, No. 1. pp. 359-366.
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abstract = "The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective δ agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The δ selective antagonist ICI 174,864 (1 μM) and the μ selective antagonist CTAP (1 μM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (δ receptors) rather than against those labeled by [3H]DAMGO (μ receptors) or [3H]U69, 593 κ receptors) in mouse whole-brain assays. The ratios of the calculated K(i) values for SNC 80 at μ/δ and κ/δ sites were 495- and 248- fold, respectively, which indicates a significant degree of δ selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95{\%} C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95{\%} C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SNC 80 antinociception was antagonized by pretreatment with i.c.v. naloxone (3 nmol), with i.c.v. or i.th. N,N-diallyl- Tyr-(Aib)2-Phe-Leu-OH(Aib=α-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindole (20 mg/kg), but not i.c.v. or i.th. β-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagonized by i.c.v. pretreatment with either [D-Ala2,Leu5,Cys6]enkephalin (a putative δ1 antagonist) or [D-Ala2, Cys4]deltorphin (a putative δ2 antagonist), but not by β-funaltrexamine (a μ antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid δ1 and δ2, but not μ, receptors. On the basis of its profile in vivo and in vitro, SNC 80 is perhaps the first highly selective, nonpeptidic and systemically active opioid δ agonist. SNC 80 promises to be a useful compound for the exploration of opioid δ-receptor pharmacology and provides a basis for the further identification of selective nonpeptidic δ ligands.",
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TY - JOUR

T1 - SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist

AU - Bilsky, E. J.

AU - Calderon, S. N.

AU - Wang, T.

AU - Bernstein, R. N.

AU - Davis, P.

AU - Hruby, Victor J

AU - McNutt, R. W.

AU - Rothman, R. B.

AU - Rice, K. C.

AU - Porreca, Frank

PY - 1995

Y1 - 1995

N2 - The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective δ agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The δ selective antagonist ICI 174,864 (1 μM) and the μ selective antagonist CTAP (1 μM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (δ receptors) rather than against those labeled by [3H]DAMGO (μ receptors) or [3H]U69, 593 κ receptors) in mouse whole-brain assays. The ratios of the calculated K(i) values for SNC 80 at μ/δ and κ/δ sites were 495- and 248- fold, respectively, which indicates a significant degree of δ selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95% C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95% C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SNC 80 antinociception was antagonized by pretreatment with i.c.v. naloxone (3 nmol), with i.c.v. or i.th. N,N-diallyl- Tyr-(Aib)2-Phe-Leu-OH(Aib=α-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindole (20 mg/kg), but not i.c.v. or i.th. β-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagonized by i.c.v. pretreatment with either [D-Ala2,Leu5,Cys6]enkephalin (a putative δ1 antagonist) or [D-Ala2, Cys4]deltorphin (a putative δ2 antagonist), but not by β-funaltrexamine (a μ antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid δ1 and δ2, but not μ, receptors. On the basis of its profile in vivo and in vitro, SNC 80 is perhaps the first highly selective, nonpeptidic and systemically active opioid δ agonist. SNC 80 promises to be a useful compound for the exploration of opioid δ-receptor pharmacology and provides a basis for the further identification of selective nonpeptidic δ ligands.

AB - The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective δ agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The δ selective antagonist ICI 174,864 (1 μM) and the μ selective antagonist CTAP (1 μM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (δ receptors) rather than against those labeled by [3H]DAMGO (μ receptors) or [3H]U69, 593 κ receptors) in mouse whole-brain assays. The ratios of the calculated K(i) values for SNC 80 at μ/δ and κ/δ sites were 495- and 248- fold, respectively, which indicates a significant degree of δ selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95% C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95% C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SNC 80 antinociception was antagonized by pretreatment with i.c.v. naloxone (3 nmol), with i.c.v. or i.th. N,N-diallyl- Tyr-(Aib)2-Phe-Leu-OH(Aib=α-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindole (20 mg/kg), but not i.c.v. or i.th. β-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagonized by i.c.v. pretreatment with either [D-Ala2,Leu5,Cys6]enkephalin (a putative δ1 antagonist) or [D-Ala2, Cys4]deltorphin (a putative δ2 antagonist), but not by β-funaltrexamine (a μ antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid δ1 and δ2, but not μ, receptors. On the basis of its profile in vivo and in vitro, SNC 80 is perhaps the first highly selective, nonpeptidic and systemically active opioid δ agonist. SNC 80 promises to be a useful compound for the exploration of opioid δ-receptor pharmacology and provides a basis for the further identification of selective nonpeptidic δ ligands.

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