PMID- 16806300
OWN - NLM
STAT- MEDLINE
DCOM- 20061214
LR  - 20181201
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 51
IP  - 3
DP  - 2006 Sep
TI  - Antinociceptive activity of chemical congeners of improgan: optimization of side 
      chain length leads to the discovery of a new, potent, non-opioid analgesic.
PG  - 447-56
AB  - Improgan is a chemical congener of the H2 antagonist cimetidine which shows the 
      profile of a highly effective analgesic when administered directly into the CNS. 
      Although the improgan receptor is unknown, improgan activates analgesic pathways 
      which are independent of opioids, but may utilize cannabinoid mechanisms. To 
      discover selective, potent, improgan-like drugs, seven compounds chemically 
      related to improgan were synthesized and tested for antinociceptive activity in 
      rats after intracerebroventricular (icv) administration. Among a series of 
      improgan congeners in which the alkyl chain length of improgan ((-CH2)3-) was 
      varied, five compounds showed full agonist antinociceptive activity with 
      potencies greater than that of improgan. VUF5420 (containing (-CH2)4-, EC50 = 
      86.1 nmol) produced maximal antinociceptive activity after doses which showed no 
      motor impairment or other obvious toxicity, and was 2.3-fold more potent than 
      improgan (EC50 = 199.5 nmol). As found previously with improgan, VUF5420-induced 
      antinociception was unaffected by administration of the opioid antagonist 
      naltrexone, but was inhibited by the CB1 antagonist SR141716A, suggesting a 
      non-opioid, cannabinoid-related analgesic action. However, VUF5420 showed very 
      low affinity (Kd approximately 10 microM) on CB1-receptor activation of 
      35S-GTPgammaS binding, indicating that this drug does not directly interact with 
      the CB1 receptor in vivo. The present results show that VUF5420 is a high 
      potency, improgan-like, non-opioid analgesic which may indirectly activate 
      cannabinoid pain-relieving mechanisms.
FAU - Hough, Lindsay B
AU  - Hough LB
AD  - Center for Neuropharmacology and Neuroscience, Albany Medical College MC-136, 
      Albany, NY 12208, USA. houghl@mail.amc.edu
FAU - de Esch, Iwan J P
AU  - de Esch IJ
FAU - Janssen, Elwin
AU  - Janssen E
FAU - Phillips, James
AU  - Phillips J
FAU - Svokos, Konstantina
AU  - Svokos K
FAU - Kern, Brian
AU  - Kern B
FAU - Trachler, Jennifer
AU  - Trachler J
FAU - Abood, Mary E
AU  - Abood ME
FAU - Leurs, Rob
AU  - Leurs R
FAU - Nalwalk, Julia W
AU  - Nalwalk JW
LA  - eng
GR  - DA-03816/DA/NIDA NIH HHS/United States
GR  - DA-09978/DA/NIDA NIH HHS/United States
GR  - DA-15915/DA/NIDA NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060623
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Analgesics)
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Cannabinoid Receptor Antagonists)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptors, Cannabinoid)
RN  - 0 (SKF 92374)
RN  - 0 (Sulfur Isotopes)
RN  - 0 (VUF5420)
RN  - 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
RN  - 80061L1WGD (Cimetidine)
RN  - RML78EN3XE (Rimonabant)
SB  - IM
MH  - Analgesics/chemical synthesis/chemistry/pharmacology
MH  - Analgesics, Non-Narcotic/chemical synthesis/*chemistry/*pharmacology
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Cannabinoid Receptor Antagonists
MH  - Cell Line
MH  - Cimetidine/*analogs & derivatives/chemical synthesis/chemistry/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics
MH  - Humans
MH  - Injections, Intraventricular/methods
MH  - Male
MH  - Pain Measurement/*drug effects
MH  - Pain Threshold/drug effects
MH  - Piperidines/pharmacology
MH  - Protein Binding/drug effects
MH  - Pyrazoles/pharmacology
MH  - Radioligand Assay
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reaction Time/drug effects
MH  - Receptors, Cannabinoid/drug effects/physiology
MH  - Rimonabant
MH  - Sulfur Isotopes/pharmacokinetics
EDAT- 2006/06/30 09:00
MHDA- 2006/12/15 09:00
CRDT- 2006/06/30 09:00
PHST- 2005/11/16 00:00 [received]
PHST- 2006/04/05 00:00 [revised]
PHST- 2006/04/06 00:00 [accepted]
PHST- 2006/06/30 09:00 [pubmed]
PHST- 2006/12/15 09:00 [medline]
PHST- 2006/06/30 09:00 [entrez]
AID - S0028-3908(06)00094-3 [pii]
AID - 10.1016/j.neuropharm.2006.04.003 [doi]
PST - ppublish
SO  - Neuropharmacology. 2006 Sep;51(3):447-56. doi: 10.1016/j.neuropharm.2006.04.003. 
      Epub 2006 Jun 23.