Irreversible blockage of opioid receptor types by ester homologs of .beta.-funaltrexamine

Abstract

A series of ester homologues 2-5 of the mu receptor nonequilibrium antagonist beta-funaltrexamine (1, beta-FNA) was synthesized. These ligands were of interest in our investigation of the relationship between the structure of the ester function and the ability to irreversibly block mu opioid receptors. While all of the ligands were potent reversible agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations, most appeared to behave as irreversible antagonists of morphine. The benzyl 5 and phenethyl 6 esters possessed irreversible mu antagonist potency that was of similar magnitude to that of beta-FNA in the GPI. In the MVD, all esters appeared to irreversibly block the agonist effect of morphine, but none of the compounds irreversibly antagonized [D-Ala2,D-Leu5]enkephalin to a significant degree. [3H]Dihydromorphine displacement studies revealed no relationship between the affinity of the esters 1-6 and the irreversible blockage of mu receptors in the GPI or MVD. Possible reasons for the observed structure-activity relationship are discussed.

Promotion of Chemical Reactions by a Grid in a Shear Mixing Layer

“…10–12 The 3‐methoxy precursors 14 a – g were also tested for comparison. Naltrindole (NTI, 1 )17, 24 and β‐FNA25 were tested in our current assays as reference compounds. New compounds were tested with [ 3 H]naltrindole, [ 3 H]DAMGO, and [ 3 H]U50,488 as the radioligands for δ, μ, and κ receptors, respectively (Table 1).…”

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

“…Naltrindole (NTI, 1) [17,24] and b-FNA [25] were tested in our current assays as reference compounds. As expected, aminothiazole-derived 14-hydroxymorphinans 7 and 8 displayed binding preference for the m receptor, a profile different from NTI (1) and indoles 3-6 which were potent and selective for the d receptor.…”

“…N-Methylimidazo[2,1-b]thiazoles 9 c-e were m-selective ligands and their functions at this single receptor were also tested. All these compounds dis- [25] ) -1 (NTI)…”

“…In view of the fact that compounds 8 and 10 both displayed high affinity at k and m receptors in spite of their significant spatial and steric differences, the primary amino group in aminothiazole 8 and the imino group in imidazo[2,1-b]thiazole 10 likely act as the k "addresser". [5,16,25] The unique position of the amino and imino nitrogen atoms in compounds 8 and 10 may also contribute to the high m binding affinity. Notably, the lipophilic tail group (thienyl) in compound 10 is located in a different position which is not observed in compounds 1, 8, or other analogues indicating that a remote lipophilic binding domain may exist for recognition of k and/or m receptor.…”

Synthesis and Tritium Labelling of 6β‐Amino‐4,5α‐epoxymorphinans and their 14‐hydroxy derivatives as potential affinity labelling probes with μ opioid agonist activity

“…The purpose of our work was to prepare opioid agonists containing an electrophilic group (methylfumaramido or chloroacetamido) at C (6). We also planned the radioactive labelling of these compounds, so we had to elaborate rapid and efficient synthetic methods .…”