Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides.
A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in delta-selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the delta address, the structural features identified to promote delta receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include hydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower mu/delta selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an overall lower delta and higher mu affinity to the piperidine-based ligands. This higher affinity for the mu receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both mu- and delta-type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the delta or mu opioid receptor.
Thomas
J B
JB
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Herault
X M
XM
Rothman
R B
RB
Atkinson
R N
RN
Burgess
J P
JP
Mascarella
S W
SW
Dersch
C M
CM
Xu
H
H
Flippen-Anderson
J L
JL
George
C F
CF
Carroll
F I
FI
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C083877:BW 373U86; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide