SYNTHESIS AND EVALUATION OF CONFORMATIONALLY RESTRICTED ENYL)ETHYL]-N-METHYL-2-(1-PYRROLIDINYL)ETHYLAMINES AT SIGMA-RECEPTORS .2. PIPERAZINES, BICYCLIC AMINES, BRIDGED BICYCLIC AMINES, AND MISCELLANEOUS COMPOUNDS

Citation
Br. Decosta et al., SYNTHESIS AND EVALUATION OF CONFORMATIONALLY RESTRICTED ENYL)ETHYL]-N-METHYL-2-(1-PYRROLIDINYL)ETHYLAMINES AT SIGMA-RECEPTORS .2. PIPERAZINES, BICYCLIC AMINES, BRIDGED BICYCLIC AMINES, AND MISCELLANEOUS COMPOUNDS, Journal of medicinal chemistry, 36(16), 1993, pp. 2311-2320
Citations number
39
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
36
Issue
16
Year of publication
1993
Pages
2311 - 2320
Database
ISI
SICI code
0022-2623(1993)36:16<2311:SAEOCR>2.0.ZU;2-0
Abstract
As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4 343) we conformationally restricted the sigma-receptor ligand N-[2-(3, 4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it int o a series of homologous piperazines 3-9 and homopiperazines 10 and 11 , diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonan es as well as other miscellaneous compounds. Sigma-receptor binding af finities were obtained using [H-3](+)-pentazocine in guinea pig brain membrane sigma1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding in teraction. Other nitrogen lone pair orientations or compounds represen ting unlikely staggered conformations of 1 [as in 4-[2-(3,4-dichloroph enyl)ethyl] -1,4-diazabicyclo[3.2.2] nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substitute d homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4- alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Comp ound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The syn thesis of ichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichloroph enyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding inter action at sigma-receptors. Sigma-receptor K(i)'s ranged from 0.55 nM f or -(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine(7) to 654 nM for 16 . Overall comparison of the results indicate that 1 is subject to cons iderable conformational freedom and suggests that the sigma receptor i s not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocycli c heterocycles.