Syntheses and Opioid Receptor Binding Affinities of 8-Amino-2,6-methano-3-benzazocines

Abstract

8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [(35)S]GTPgammaS assays.

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

“…Removal of N- trifluoroacetyl group was performed in refluxing MeOH leading to the final compound 13 . 32 In order to make sulfonamides and amides ( 14a–f ), compound 9d and (+)- 9d were reacted with corresponding sulfonyl chlorides and benzoyl/acetyl chlorides in the presence of pyridine to yield sulfonamides 14a–f and ( + )- 14f . 33 …”

Twin and Triplet Drugs in Opioid Research

“…A good relationship between the affinities and the number of methylene units in the ester linker was observed and compound 13b with eight methylene units showed the highest affinity among analogs with two to ten methylene units except for compound 13a with an ethylene unit or 17 with a vinylene unit. In the functional assay ([ 35 S]GTPgS binding assay), compounds 13a and 13b were partial m agonists and full k agonists ( 50 ¼ 0.27 nmol) in the mouse warm-water-tail-flick test, and its activities were more potent than butorphan (6) itself (ED 50 ¼ 7.3 nmol) and equipotent to morphine. Antinociceptive effects induced by 17 were blocked by an i.c.v.…”

Kappa-opioid receptor ligands

“…Cyclazocine (13a) has been evaluated for this purpose, although it appears, amongst other things, an extended duration of action would be desirable. To this end Wentland (Rensselaer Polytechnic Institute) [107] has replaced the phenolic hydroxyl group of cyclazocine and related benzomorphans and morphinans, which is prone to rapid sulfonylation and glucuronidation, with amino, carboxamido, thiocarboxamido, hydroxyamidino and formamide moieties in order to decrease the rate of metabolism and increase duration of activity in vivo ( Table 7) [45][46][47][48]. The carboxamido (13c) and thiocarboxamido (13d) groups were particularly impressive in their ability to retain high affinity for each of the opioid receptors in the cyclazocine series.…”