We designed highly selective non-peptide agonists for the delta-opioid receptor. On the basis of the "message-address" concept in this field and the accessory site hypothesis, a novel class of heterocycle-fused octahydroisoquinoline derivatives were synthesized. One of these compounds [(4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12, 12a -octahydropyrido[3,4-b]acridine, TAN-67 (2)] showed high selectivity for the delta-opioid receptor (Ki = 1.12 nM) in guinea-pig cerebrum with a 2070-fold lower affinity for the mu-opioid receptor and a 1600-fold lower affinity for the kappa-opioid receptor. TAN-67 was a potent delta-opioid receptor agonist with an IC50 value of 6.61 nM in the mouse vas deferens assay that was reversed by naltrindole (NTI) (Ke = 0.21). Moreover, TAN-67 was shown to have antinociceptive activity following subcutaneous administration in the mouse acetic acid abdominal constriction assay that was antagonized by NTI (delta 1- and delta 2-antagonist) and 7-benzylidinenaltrexone (delta 1-antagonist), but not by naltriben (delta 2-antagonist). This systemically applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the delta-opioid receptor.
Novel cyclo-oligomerization of nickel methylenecarbenoids generated from 1 ,I -dihalogenoethenes with chemically activated nickel gives [3]-, [4]-, and [5]-radialenes directly under mild conditions.Radialenes (polymethylenecycloalkanes) have attracted considerable interest from the scientific community because they can serve as electron donors and acceptors for organic metals and ferromagnets,l and have particular arrangements of n-electrons.2 In conjunction with our program to develop methods for transition-metal-catalysed synthesis of new n-electron systems,3 we previously reported a novel method for preparing radialenes by cyclo-oligomerization of the ate-type complexes derived from lithium carbenoids with an appropriate copper(1) complex.4Metal methylenecarbenoids are known to give acetylenes via methylenecarbenes (Fritsch-Buttenbery-Wiechell rearrangement)s or to afford dimerized [3]cumulenes (butatrienes).6 We report here a novel cyclo-oligomerization of nickel methylenecarbenoids to produce radialenes.The activated metallic nickel7 was prepared by reduction of NiI2 with 0 . 7 4 . 8 equiv. of lithium powder and 0.1 equiv. of 4,4'-di-t-butylbiphenyl as an electron carrier in tetrahydrofuran (THF) under sonication (30-40 "C) and used directly.-a. e+MeA Me Ar Ar Ar Ar Me +Ax Me Ar Me Ar (7) *
Nickel-catalyzed cyclo-oligomerization of aryl-substituted 1,1-dibromoethylenes in the presence or absence of diarylacety-lenes produces 1,2,3,4,6,6-hexaarylfulvenes and/or 1,2-diaryl-3,4-bis(diarylmethylene)cyclobutenes in moderate yields, providing a new and simple method for C6Ar6 conjugated hydrocarbons, highly overcrowded systems.
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