Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans

Subramaniam Ananthan, Hollis S. Kezar, Ronald L. Carter, Surendra K. Saini, Kenner C. Rice, Jennifer L. Wells, Peg Davis, Heng Xu, Christina M. Dersch, Edward J. Bilsky, Frank Porreca, Richard B. Rothman

Research output: Contribution to journalArticle

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Abstract

A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid δ, μ, and K receptors with K1 values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and GPI with K(e) values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and δ receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative 5 address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4'-position of 6a or the equivalent 6'- position of 7a led to dramatic reduction in binding potencies at all the three opioid receptors, indicating the existence of a somewhat similar steric constraint at the ligand binding sites of δ, μ, and κ receptors. In contrast, the introduction of a phenyl group at the 5'-position of 6a did not cause any reduction in the binding affinity at the δ receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in μ/δ and κ/δ binding selectivity ratios as well as in the δ antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in δ antagonist potency in the MVD but also shifted the intrinsic activity profile of 6c from an antagonist to that of a μ agonist in the GPI. Compound 6d thus possesses the characteristics of a nonpeptide μ agonist/δ antagonist ligand with high affinity at the δ receptor (K1 = 2.2 nM), high antagonist potency in the MVD (K(e) = 0.66 nM), and moderate agonist potency in the GPI (IC50 = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 °C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A50 = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icy injections of an A90 dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent δ antagonist component of this mixed μ agonist/δ antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays.

Original languageEnglish (US)
Pages (from-to)3527-3538
Number of pages12
JournalJournal of Medicinal Chemistry
Volume42
Issue number18
DOIs
StatePublished - Sep 9 1999

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Naltrexone
Opioid Receptors
Bioactivity
Vas Deferens
Assays
Ligands
Ileum
Acetic Acid
Guinea Pigs
Chlorine
Opioid Analgesics
Toxicity
Display devices
Binding Sites
Atoms
Injections
Inhibitory Concentration 50
pyridine
Tail

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Ananthan, S., Kezar, H. S., Carter, R. L., Saini, S. K., Rice, K. C., Wells, J. L., ... Rothman, R. B. (1999). Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans. Journal of Medicinal Chemistry, 42(18), 3527-3538. https://doi.org/10.1021/jm990039i

Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans. / Ananthan, Subramaniam; Kezar, Hollis S.; Carter, Ronald L.; Saini, Surendra K.; Rice, Kenner C.; Wells, Jennifer L.; Davis, Peg; Xu, Heng; Dersch, Christina M.; Bilsky, Edward J.; Porreca, Frank; Rothman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 42, No. 18, 09.09.1999, p. 3527-3538.

Research output: Contribution to journalArticle

Ananthan, S, Kezar, HS, Carter, RL, Saini, SK, Rice, KC, Wells, JL, Davis, P, Xu, H, Dersch, CM, Bilsky, EJ, Porreca, F & Rothman, RB 1999, 'Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans', Journal of Medicinal Chemistry, vol. 42, no. 18, pp. 3527-3538. https://doi.org/10.1021/jm990039i
Ananthan, Subramaniam ; Kezar, Hollis S. ; Carter, Ronald L. ; Saini, Surendra K. ; Rice, Kenner C. ; Wells, Jennifer L. ; Davis, Peg ; Xu, Heng ; Dersch, Christina M. ; Bilsky, Edward J. ; Porreca, Frank ; Rothman, Richard B. / Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 18. pp. 3527-3538.
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T1 - Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans

AU - Ananthan, Subramaniam

AU - Kezar, Hollis S.

AU - Carter, Ronald L.

AU - Saini, Surendra K.

AU - Rice, Kenner C.

AU - Wells, Jennifer L.

AU - Davis, Peg

AU - Xu, Heng

AU - Dersch, Christina M.

AU - Bilsky, Edward J.

AU - Porreca, Frank

AU - Rothman, Richard B.

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N2 - A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid δ, μ, and K receptors with K1 values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and GPI with K(e) values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and δ receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative 5 address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4'-position of 6a or the equivalent 6'- position of 7a led to dramatic reduction in binding potencies at all the three opioid receptors, indicating the existence of a somewhat similar steric constraint at the ligand binding sites of δ, μ, and κ receptors. In contrast, the introduction of a phenyl group at the 5'-position of 6a did not cause any reduction in the binding affinity at the δ receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in μ/δ and κ/δ binding selectivity ratios as well as in the δ antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in δ antagonist potency in the MVD but also shifted the intrinsic activity profile of 6c from an antagonist to that of a μ agonist in the GPI. Compound 6d thus possesses the characteristics of a nonpeptide μ agonist/δ antagonist ligand with high affinity at the δ receptor (K1 = 2.2 nM), high antagonist potency in the MVD (K(e) = 0.66 nM), and moderate agonist potency in the GPI (IC50 = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 °C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A50 = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icy injections of an A90 dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent δ antagonist component of this mixed μ agonist/δ antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays.

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