Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.
Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.
Glennon
R A
RA
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
Ismaiel
A M
AM
Smith
J D
JD
Yousif
M
M
el-Ashmawy
M
M
Herndon
J L
JL
Fischer
J B
JB
Howie
K J
KJ
Server
A C
AC
D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D008861:Microsomes / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism*; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma; D013379:Substrate Specificity
D011437:Propylamines; D011957:Receptors, Opioid; D017480:Receptors, sigma; C068473:N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane; D010622:Phencyclidine