A new approach to the design of .sigma.-2-selective ligands: synthesis and evaluation of N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine-related polyamines at .sigma.-1 and .sigma.-2 receptor subtypes

• Published in: Journal of medicinal chemistry Vol. 37; no. 2; pp. 314 - 321
• Main Authors: de Costa, Brian R, He, Xiao-shu, Dominguez, Celia, Cutts, Janet, Williams, Wanda, Bowen, Wayne D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.01.1994; Amer Chemical Soc
• Subjects: Animals; Binding Sites; Brain - metabolism; Chemistry; Chemistry, Medicinal; Drug Design; Ethylamines - chemical synthesis; Ethylamines - chemistry; Ethylamines - pharmacology; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; In Vitro Techniques; Life Sciences & Biomedicine; Ligands; Liver - metabolism; Male; Molecular Structure; Organic chemistry; Pharmacology & Pharmacy; Polyamines - chemical synthesis; Polyamines - chemistry; Polyamines - pharmacology; Preparations and properties; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, sigma - drug effects; Receptors, sigma - metabolism; Science & Technology; AGENTS; RAT; BINDING-SITES; ANALOGS; AFFINITY; BRAIN; Chemical reduction; Five membered ring; Polyamine; Structure activity relation; Nitrogen heterocycle; Sigma receptor; Affinity; Acylation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00028a016

A series of polyamines based on the high affinity sigma receptor ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were developed and evaluated for their binding characteristics at sigma-1 and sigma-2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at a receptors; As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes. Although additional nitrogen atoms resulted in decreased affinity at sigma-1 and sigma-2 subtypes, an increase in selectivity for sigma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on binding affinity and subtype selectivity. For example, the difference between N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N,N'-dimethylethylenediamine (8) [K-i = 29.9 nM at sigma-1 receptor and 18.3 nM at alpha-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N/N'-dimethylethylenedi- amine (10) [K-i = 1.49 nM at sigma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the importance of internitrogen spacing. Triamines 11 and 13 [K-i(sigma-2)/K-i(sigma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacings 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These compounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of the polyamines tested in this series) proved to be an important recognition site for a receptor binding activity. Furthermore, alkyl substitution also appears to be important since the stripped down polyamines N-[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N-1-[2-(3,4-dichlorophenyl)ethyl] diethylenetriamine (16) exhibited relatively low binding affinity.