Probes for Narcotic Receptor-Mediated Phenomena. 20. Alteration of Opioid Receptor Subtype Selectivity of the 5-(3-Hydroxyphenyl)morphans by Application of the Message-Address Concept: Preparation of .delta.-Opioid Receptor Ligands

Abstract

Derivatives of racemic and optically active 5-(3-hydroxyphenyl)-2-methylmorphan (5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1) were synthesized containing additional aromatic moieties, as an application of the message-address concept targeted at producing delta-opioid receptor selective ligands. In vitro radioreceptor binding studies in rat brain revealed that both of the parent enantiomers, (-)- and (+)-1, had a high affinity for the mu-opioid receptor (21 nM), a slight affinity for kappa 1-opioid receptors (approximately 800-900 nM), and less than 1000 nM affinity for the delta-opioid receptor (mu/delta IC50 ratio of < 0.02 for both). A derivative of (-)-1 containing an indole moiety fused at the C6-C7 position of the phenylmorphan nucleus, (-)-11, displayed a > 180-fold increase in affinity for the delta-opioid receptor with an IC50 value of 6 nM. The parent compound (-)-1 had only 26% agonist activity at 30 microM in the mouse vas deferens (delta) bioassay, whereas compound (-)-11 had an IC50 of 393 nM in this preparation, indicating the importance of the indole moiety in imparting delta-opioid agonist activity to the phenylmorphan (-)-11. A structure-activity relationship (SAR) study of N-alkyl derivatives of the racemic nor 11 indicated similarities between the interaction of various derivatives with the mu- and delta- but not the kappa 1-opioid receptor. As studies on the molecular basis of the interaction of opioid ligands with their respective receptors continue to gain momentum, the SAR data described herein for the synthetic phenylmorphans will prove useful for further studies.

Discovery of an Opioid κ Receptor Selective Pure Antagonist from a Library of N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphans

“…Reduction of 9 using sodium and 2-propanol in refluxing toluene gave 10 in 54% yield. 10 Removal of the isopropyl group in 10 using 48% hydrobromic and glacial acetic acid then provided the 7-amino-derivatized scaffold (11) in 84% yield.…”

Diastereoselective One-Pot Synthesis of 7- and 8-Substituted 5-PhenylmorphansProbes for Narcotic Receptor Mediated Phenomena. 45.

“…In order to determine what pharmacological profile would be conferred by substituents at the C-7 or C-8 positions we needed to find a synthetic path to these less accessible compounds. Only 7-amino 4 and 6,7- and 7,8-fused indole derivatives 5 synthesized from 7-keto-5-phenylmorphan, and C3 and C7-alkyl or alkenyl 5-phenylmorphans have been reported thus far, the latter by Zimmerman 6 who used a phosphoric acid/formic acid mixture and did not assign the stereochemistry of his products.…”

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

“…The question of what that "correct" δ/µ ratio might be has not as yet been answered. Our previous attempts to determine this in the 5-phenylmorphan series failed due to their lack of potency [19,20]. There have been many reports of lessened side-effects induced by bifunctional ligands, mostly reduced gastrointestinal effects, a few equivocal results on reduced tolerance and dependence, and other reports have indicated reduced respiratory depression [21][22][23][24][25][26][27].…”