115200-95-8Relevant academic research and scientific papers
Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the σ receptor
De Costa,Radesca,Di Paolo,Bowen
, p. 38 - 47 (2007/10/02)
By synthesizing and testing a part-structure, N-[2-(3,4- dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3), derived from our previously reported high affinity σ receptor ligands (1S,2R)-(-)-N-[2- (3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine [(-)- 2] and (+)-2, we have identified a novel class of superpotent (subnanomolar affinity) σ ligands specific for the σ receptor labeled by [3H]-(+)-3-PPP. When 3 was tested for its capacity to displace [3H]-(+)-3-PPP from guinea pig brain membranes, it exhibited a K(i) of 0.34 nM, which is better than either of its parent compounds (-)-2 (K(i) = 1.3 nM) and (+)-2 (K(i) = 6.0 nM). Other compounds related to 3 such as N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(1-homopiperidinyl)ethylamine (19) exhibited K(i) = 0.17 nM ([3H]- (+)-3-PPP). The determinants for high σ receptor affinity of 3 were examined by manipulation of this structure in a number of different ways. The high efficacy of these compounds for the σ receptor, their relative chemical simplicity and ease of synthesis, and their high degree of selectivity identifies N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine (3) and related compounds as a highly promising base for determination of the functional role of σ receptors as well as the development of novel therapeutic agents.
Structure/Activity Studies Related to 2-(3,4-Dichlorophenyl)-N-methyl-N-acetamides: A Novel Series of Potent and Selective κ-Opioid Agonists
Barlow, Jeffrey J.,Blackburn, Thomas P.,Costello, Gerard F.,James, Roger,Count, David J. Le,et al.
, p. 3149 - 3158 (2007/10/02)
This paper describes the synthesis of a series of N-acetamides 1, variously substituted at the carbon adjacent to the amide nitrogen (C1), and related analogues, together with their biological evaluation as opioid κ agonists.In the first part of the study, the variants in N-acyl, N-alkyl, and amino functions were explored when the substituent at C1 was 1-methylethyl and the optimum was found to be exemplified by 2-(3,4-dichlorophenyl)-N-methyl-N-acetamide (13).Subsequently, racemic or chiral amino acids were used to introduce other alkyl and aryl substituents at C1 of the ethyl linking moiety.A series of potent compounds, bearing substituted-aryl groups at C1, were discovered, typified by 2-(3,4-dichlorophenyl)-N-methyl-N-acetamide (48), which was 5-fold more active as the racemate than 13 in vitro and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.04 mg/kg sc) in a mouse abdominal constriction model.
