Effects of Substitution on the Pyrrole N Atom in Derivatives of Tetrahydronaltrindole, Tetrahydrooxymorphindole, and a Related 4,5-Epoxyphenylpyrrolomorphinan

Abstract

The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI), tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4'-phenyl-6,7:2',3'-pyrrolomorphinan (4) is reported. In opioid functional assays 4 were potent deltaopioid receptor (DOR) antagonists while the TNTI derivatives (7) were potent DOR antagonists or low-efficacy DOR partial agonists without substantial selectivity. The TOMI derivatives (8) were DOR agonists with significant selectivity. In vivo the DOR antagonist activity of 7d was confirmed, but the predominant agonist effect of 8d was shown to be mu opioid receptor mediated.

Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones

“…Among them, pyrroles have a distinguished position in the chemistry of living organisms due to their close biogenetic connection to the porphyrins, the chlorins, and the corrins. Furthermore, they are regarded as privileged structures by synthetic chemists because of widespread applications in medicinal chemistry [2–3] and materials science [4]. Not surprisingly, numerous synthetic methods [5–27] are still being developed for this compound class although many classical methods such as Hantzsch [28], Knorr [29], Paal–Knorr [30], and Barton–Zard [31] have already found their way into the textbooks of organic chemistry.…”

2,4- vs 3,4-Disubsituted Pyrrole Synthesis Switched by Copper and Nickel Catalysts

“…Pyrroles are one of the important classes of heterocyclic compounds as well as building blocks in many synthetic pharmaceutical agents, natural products, and materials science . Various synthetic methods have been developed for the construction of pyrrole structures. , However, most known approaches are effective for 2,5-di- or polysubstituted pyrroles .…”

Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

“…6, 7 With maleic anhydride the products were the 5′-hydroxypyrrolomorphinans ( 4 ); reaction with ethyl acrylate, methyl methacrylate and α-methylene-γ-butyrolactone gave pyridomorphinans of general structure 5 . 6 The pharmacological evaluation of these ligands was not reported.…”