Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans
Autore:
Ananthan, S; Kezar, HS; Carter, RL; Saini, SK; Rice, KC; Wells, JL; Davis, P; Xu, H; Dersch, CM; Bilsky, EJ; Porreca, F; Rothman, RB;
Indirizzi:
So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA So Res Inst Birmingham AL USA 35255 Organ Chem, Birmingham, AL 35255 USA NIDA, Clin Psychopharmacol Sect, DIR, Baltimore, MD 21224 USA NIDA Baltimore MD USA 21224 opharmacol Sect, DIR, Baltimore, MD 21224 USA NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA NIDDKD Bethesda MD USA 20892 D, Med Chem Lab, NIH, Bethesda, MD 20892 USA Univ No Colorado, Dept Biol Sci, Greeley, CO 80639 USA Univ No Colorado Greeley CO USA 80639 ept Biol Sci, Greeley, CO 80639 USA Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA Univ ArizonaTucson AZ USA 85724 ed, Dept Pharmacol, Tucson, AZ 85724 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 18, volume: 42, anno: 1999,
pagine: 3527 - 3538
SICI:
0022-2623(19990909)42:18<3527:SORBAB>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
MESSAGE ADDRESS CONCEPT; PHARMACOLOGICAL CHARACTERIZATION; NALTRINDOLE 5'-ISOTHIOCYANATE; DIFFERENTIAL ANTAGONISM; MORPHINE-TOLERANCE; AGONIST; AFFINITY; DEPENDENCE; SUBTYPES; SELECTIVITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Ananthan, S So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA So Res Inst Birmingham AL USA 35255 Birmingham, AL 35255 USA
Citazione:
S. Ananthan et al., "Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans", J MED CHEM, 42(18), 1999, pp. 3527-3538

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 delta, mu, and kappa receptors with Ki values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mousevas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and CPI with K-e values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and 6 receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative 6 address mimics on the pyrido- and pyrimidomorphinan framework gave ligands withsignificant 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 delta, mu, and kappa receptors. In contrast, the introduction of a phenyl group at the 6'-position of 6a did not cause any reduction in the binding affinity at the 6 receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in mu/delta and kappa/delta binding selectivity ratios as well as in the 6 antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not onlyprovided further improvements in 6 antagonist potency in the MVD but also shifted the intrinsic activity profile of sc from an antagonist to that of a mu agonist in the GPI. Compound Sd thus possesses the characteristics of a nonpeptide mu agonist/delta antagonist ligand with high affinity at the 6receptor (Ki = 2.2 nM), high antagonist potency in the MVD (K-e, = 0.66 nM), and moderate agonist potency in the GPI (IC50 = 163 nM). Antinociceptiveevaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 degrees C tail-flick assayand a full agonist effect in the acetic acid writhing assay (A(50) = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icy injections of an A(90) dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent 6 antagonist component of this mixed mu agonist/delta antagonist may be responsible for the diminished propensityto produce tolerance that this compound displays.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/04/20 alle ore 23:12:32