111469-81-9Relevant academic research and scientific papers
Fischer indole synthesis in water: Simple, efficient preparation of naltrindole, naltriben and analogs
Duval, Romain A.,Lever, John R.
experimental part, p. 304 - 309 (2011/02/28)
Naltrindole, naltrindole analogs and the benzofuran congener naltriben have been prepared by Fischer syntheses using mildly acidic, purely aqueous conditions. The preparation of naltrindole and several analogs was accomplished under almost neutral conditions using just the hydrochloride salts of naltrexone and various electron-rich and electron-poor phenylhydrazines in boiling water. The products were obtained by simple filtration in good to excellent yields and with high purities in the majority of cases. The route is suited to gram-scale synthesis, does not require the use of organic solvents, minimizes the use of corrosive acids, and is simple, efficient and environmentally friendly. Naltriben was prepared efficiently from the hydrochloride salts of naltrexone and O-phenylhydroxylamine but more forcing conditions, 6.0 N HCl, were required. A limitation to the method is the failure of Fischer cyclization between naltrexone and nitro-substituted phenylhydrazines under aqueous conditions.
Design of peptidomimetic δ opioid receptor antagonists using the message-address concept
Portoghese,Sultana,Takemori
, p. 1714 - 1720 (2007/10/02)
Highly selective nonpeptide ligands with potent δ opioid receptor antagonist activity have been developed using the message-address concept. This approach envisaged the δ opioid receptor to contain two major recognition subsites; a message subsite which recognizes the pharmacophore, and an address subsite that is unique for the δ receptor type and confers selectivity. The message and address components of the δ-selective enkephalins were postulated to be Tyr1 and Phe4, respectively, with Gly2-Gly3 functioning as a spacer. The message component of the target compounds in this study was derived from naltrexone and related structures. An indole system was fused to the C ring of naltrexone as a mimic of the address component. The benzene moiety of indole was viewed as the δ address component, mimicking the phenyl group of Phe4, and the pyrrole portion was used as a rigid spacer. Members of the series (1-23) were evaluated for opioid antagonist activity on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Naltrindole (NTI, 1) was the most potent member of the series, with K(e) values of ~0.1 nM at δ receptors. The antagonism by NTI was ~220- and 350-fold greater at δ than at μ and κ opioid receptors. The binding of NTI and selected members of the series to guinea pig brain membranes was qualitatively consistent with their pharmacologic antagonist activity profiles in the MVD and GPI, but the K(i) values were not in the same rank order. The selectivity of NTI arises mainly as a consequence of increased affinity at δ receptors. Thus, the K(e) and K(i) values of NTI were 1/530 and 1/90 that of the δ antagonist enkephalin analogue, ICI 174864. In contrast to NTI, ICI174864 derives its selectivity through greatly decreased recognition at μ and κ receptors. The implications of the high affinity and selectivity of NTI as a consequence of its conformational rigidity are discussed. It is suggested that any attempt to model a receptor-bound conformation of an opioid peptide should consider affinity and potency at multiple receptor sites rather than selectivity alone.
