Differential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists.
In in vitro studies, SR 48692, a nonpeptide neurotensin receptor antagonist, inhibited the binding of [3H] or [125I]neurotensin to membrane preparations from 10-day-old mouse brains and from HT-29 cells with Ki values of 3.9 and 8.6 nM, respectively. SR 48692 also antagonized the neurotensin-induced mobilization of intracellular calcium in HT-29 cells, in agreement with previous findings. In rat cerebellar slices SR 48692 blocked the increase in cyclic GMP levels evoked by neurotensin in a dose-dependent manner. In vivo, SR 48692 antagonized the increase in rat brain mesolimbic dopamine turnover induced by the systemically active neurotensin peptide, EI [(N-Me)Arg-Lys-Pro-Trp-tert-Leu-Leu]. No effects on dopamine turnover of either EI or SR 48692 were observed in the striatum. SR 48692 did not antagonize the EI-induced decreases in mouse body temperature and spontaneous locomotor activity (LMA) or the decreases in LMA induced by ICV-administered neurotensin. Although other explanations are possible, these findings support the hypothesis that a subtype of the NT receptor may mediate the locomotor and hypothermic actions of this peptide and that it is different from the NT receptor that is involved in dopamine turnover.
Pugsley
T A
TA
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, MI 48105, USA.
Akunne
H C
HC
Whetzel
S Z
SZ
Demattos
S
S
Corbin
A E
AE
Wiley
J N
JN
Wustrow
D J
DJ
Wise
L D
LD
Heffner
T G
TG
D000818:Animals; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D006152:Cyclic GMP / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009496:Neurotensin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats
D009842:Oligopeptides; D011619:Psychotropic Drugs; D011720:Pyrazoles; D011804:Quinolines; C068951:methyl(arginyl)-lysyl-prolyl-tryptophyl-tert-leucyl-leucine; C079087:SR 48692; D009496:Neurotensin; D006152:Cyclic GMP; D002118:Calcium; D004298:Dopamine