N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues.
The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.
Wei
Z Y
ZY
Departments of Chemistry and Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec, Canada H4S 1Z9. john.wei@astrazeneca.com
Brown
W
W
Takasaki
B
B
Plobeck
N
N
Delorme
D
D
Zhou
F
F
Yang
H
H
Jones
P
P
Gawell
L
L
Gagnon
H
H
Schmidt
R
R
Yue
S Y
SY
Walpole
C
C
Payza
K
K
St-Onge
S
S
Labarre
M
M
Godbout
C
C
Jakob
A
A
Butterworth
J
J
Kamassah
A
A
Morin
P E
PE
Projean
D
D
Ducharme
J
J
Roberts
E
E
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014162:Transfection
D001549:Benzamides; C415566:N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide; D010879:Piperazines; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide