PMID- 15994087
OWN - NLM
STAT- MEDLINE
DCOM- 20051028
LR  - 20181201
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 13
IP  - 18
DP  - 2005 Sep 15
TI  - Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist 
      N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide 
      (SR141716) with unique binding selectivities and pharmacological activities.
PG  - 5463-74
AB  - An extended series of alkyl carboxamide analogs of 
      N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 
      1H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested 
      for its ability to displace the prototypical cannabinoid ligands ([3H]CP-55,940, 
      [3H]2; [3H]SR141716, [3H]5; and [3H]WIN55212-2, [3H]3), and selected compounds 
      were further characterized by determining their ability to affect guanosine 
      5'-triphosphate (GTP)-gamma-[35S] binding and their effects in the mouse vas 
      deferens assay. This systematic evaluation has resulted in the discovery of novel 
      compounds with unique binding properties at the central cannabinoid receptor 
      (CB1) and distinctive pharmacological activities in CB1 receptor tissue 
      preparations. Specifically, compounds with nanomolar affinity which are able to 
      fully displace [3H]5 and [3H]2, but unable to displace [3H]3 at similar 
      concentrations, have been synthesized. This selectivity in ligand displacement is 
      unprecedented, in that previously, compounds in every structural class of 
      cannabinoid ligands had always been shown to displace each of these radioligands 
      in a competitive fashion. Furthermore, the selectivity of these compounds appears 
      to impart unique pharmacological properties when tested in a mouse vas deferens 
      assay for CB1 receptor antagonism.
FAU - Thomas, Brian F
AU  - Thomas BF
AD  - Science and Engineering Group, Research Triangle Institute, Research Triangle 
      Park, NC 27709, USA.
FAU - Francisco, Maria Elena Y
AU  - Francisco ME
FAU - Seltzman, Herbert H
AU  - Seltzman HH
FAU - Thomas, James B
AU  - Thomas JB
FAU - Fix, Scott E
AU  - Fix SE
FAU - Schulz, Anne-Kathrin
AU  - Schulz AK
FAU - Gilliam, Anne F
AU  - Gilliam AF
FAU - Pertwee, Roger G
AU  - Pertwee RG
FAU - Stevenson, Leslie A
AU  - Stevenson LA
LA  - eng
GR  - DA-09789/DA/NIDA NIH HHS/United States
GR  - DA-19217/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Amides)
RN  - 0 (Cyclohexanols)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 83003-12-7 
      (3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol)
RN  - RML78EN3XE (Rimonabant)
SB  - IM
MH  - Amides/chemical synthesis/*chemistry/*pharmacology
MH  - Animals
MH  - Binding Sites
MH  - Brain/cytology
MH  - Cell Membrane/chemistry
MH  - Cyclohexanols/metabolism/pharmacology
MH  - Humans
MH  - Mice
MH  - *Piperidines/chemical synthesis/chemistry/pharmacology
MH  - *Pyrazoles/chemical synthesis/chemistry/pharmacology
MH  - Rats
MH  - Receptor, Cannabinoid, CB1/*antagonists & inhibitors/metabolism
MH  - Rimonabant
EDAT- 2005/07/05 09:00
MHDA- 2005/10/29 09:00
CRDT- 2005/07/05 09:00
PHST- 2004/11/18 00:00 [received]
PHST- 2005/05/31 00:00 [revised]
PHST- 2005/06/01 00:00 [accepted]
PHST- 2005/07/05 09:00 [pubmed]
PHST- 2005/10/29 09:00 [medline]
PHST- 2005/07/05 09:00 [entrez]
AID - S0968-0896(05)00512-2 [pii]
AID - 10.1016/j.bmc.2005.06.005 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2005 Sep 15;13(18):5463-74. doi: 10.1016/j.bmc.2005.06.005.