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

Abstract

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 sigma 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 sigma-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)- N,N'-dimethylethylenediamine (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 [Ki(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 sigma 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 N1-[2-(3,4-dichlorophenyl)ethyl]diethylenetriamine (16) exhibited relatively low binding affinity.

σ1 and σ2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503

“…The r 1 selectivity observed for SA4503 is 10 to 1 based upon IC 50 ratios, and 14 to 1 using K i values despite the higher r 1 affinity of SA4503 in our hands (6.67 nM vs. 17.4 nM IC 50 ). We and others (Cobos et al, 2005;de Costa et al, 1994;DeHaven-Hudkins et al, 1992), also note 3-to 5-fold higher r 1 affinities than Matsuno et al (1996), reported for the reference compounds (þ)-pentazocine (IC 50 ¼ 13.7 nM) and DTG (IC 50 ¼ 246 nM) in the original SA4503 work. This suggests a systematic, but not easily distinguished, difference between the r 1 receptor assays.…”

Re‐evaluation of phencyclidine low‐affinity or “non‐NMDA” binding sites

“…FE93, GK171, FE114, and Ifenprodil were of particular interest, since they exhibited both a high affinity and high selectivity (1,000 to 5,000 times) for PCP 3 binding sites. It is worth noting that the σ 2 (BD1008, Ifenprodil) and the σ 3 (BD737) but not the σ 1 (BD1063) receptor ligands potently interacted with these binding sites (De Costa et al, 1994; Hashimoto and London, 1995; Matsumoto et al, 1995; Monnet et al, 1996). Memantine and CNS1102, two compounds that are currently investigated as potential neuroprotective drugs (Kornhuber et al, 1994; Hu et al, 1997), also displayed a high affinity for PCP 3 binding sites but with a lower selectivity.…”

“…As a matter of fact, BD1008 did not prevent the specific binding of (−)[ 3 H]GK11 to the “non‐NMDA” binding site but slightly inhibited that of [ 3 H]TCP in the forebrain and the molecular layer of the cerebellum. This effect might represent a low‐affinity interaction of [ 3 H]TCP with sigma receptors, since BD1008 was primarily developed as a sigma ligand (De Costa et al, 1994). Indeed, the region‐dependent effect of BD1008 on [ 3 H]TCP specific binding is consistent with the known preferential expression of sigma receptors in the forebrain and the molecular layer of the cerebellum (Largent et al, 1986; Jansen et al, 1991).…”

Classes of Sigma2 (σ2) Receptor Ligands: Structure Affinity Relationship (SAfiR) Studies and Antiproliferative Activity

“…At that time, only a few other compounds were known to display a certain 2 over 1 receptor selectivity. Compounds belonging to the pyrrolidinyl-and carboline-derivatives classes were characterized by a low (at the best around 10-fold) 2 versus 1 receptor selectivity [16,17], far from the excellent selectivity displayed by (+)-morphans. However, opioid and 2 receptors displayed the same enantioselectivity, so that CB64D and CB184 were accompanied also by high opioid affinity displaying just moderate 2 versus opioid receptors selectivity.…”