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
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
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.