SR 142948A

SR 142948A is a blood-brain barrier-permeable, orally active, selective, non-peptide Neurotensin Receptor antagonist. SR 142948A exhibits an IC₅₀ of 4.0 nM at the NTS1 site. SR 142948A competitively antagonizes neurotensin-dependent neurotransmitter release and modulates neurotensin-related dopaminergic and serotonergic signaling, making it useful for research on neurobehavioral mechanisms associated with schizophrenia^{[1][2][3][4][5][6][7][8][9]}. In Vitro:SR 142948A (60 min) displaces [³H]SR 142948A in a concentration-dependent manner in rat brain membrane homogenate competitive binding assays, with a K_i of 5.0 nM^[1].
SR 142948A (60 min; 10 μM Levocabastine (HY-14277)) exhibits an IC₅₀ of 4.0 nM for Levocabastine-insensitive NTS1 sites in rat brain membrane homogenates, whereas the IC₅₀ is 7.0 nM for total NT1+NT2 sites in the absence of Levocabastine^[1].
SR 142948A (3-100 nM) concentration-dependently right-shifts the neurotensin concentration-response curve in rat frontal cortex slices, with an apparent pA₂ of 8.3; at 30 nM, it reduces the maximal effect of 1 μM neurotensin by 24%, and in a classical inhibition curve, it exhibits an IC₅₀ of 4.5 nM against 100 nM neurotensin-induced K⁺-evoked [³H]5-HT release^[2].
SR 142948A (3-100 nM) alone does not alter spontaneous or K⁺-evoked [³H]5-HT release in rat frontal cortex slices^[2]. In Vivo:SR 142948A (0.1 mg/kg; i.p.; single administration; 1 h before testing) does not alter the acoustic startle amplitude of alone pulse stimuli in female Long-Evans rats on diestrus day 1 or proestrus; SR 142948A decreases prepulse inhibition (PPI) in both estrous cycle stages at 13:00, decreases PPI in proestrus at 01:00, but increases PPI on diestrus day 1^[3].
SR 142948A (0.03-0.1 mg/kg; i.p.; single administration) does not alter spontaneous locomotor activity or psychostimulant-induced hyperactivity in male CD1 mice^[4].
SR 142948A (0.03-0.1 mg/kg; i.p.; single administration; 10 min before Haloperidol (HY-14538) administration) attenuates 0.01 mg/kg Haloperidol-induced hypoactivity in male CD1 mice; 0.03 and 0.05 mg/kg are effective, with 0.05 mg/kg restoring locomotor activity to vehicle control levels, whereas 0.1 mg/kg shows no clear reversal effect^[4].
SR 142948A (0.03-0.1 mg/kg; i.p.; single administration; combined with 0.04 mg/kg Haloperidol and psychostimulant challenge) attenuates the suppression of psychostimulant-induced hyperactivity by Haloperidol, with 0.03 and 0.05 mg/kg being effective but not fully reversing the effect of Haloperidol^[4].
SR 142948A (0.03-0.1 mg/kg; i.p.; single administration; 10 min before Haloperidol administration) enhances 0.3 mg/kg Haloperidol-induced catalepsy, with 0.05 and 0.1 mg/kg being effective, whereas 0.03 mg/kg shows no clear effect^[4].
SR 142948A (10 μg/kg; i.p.; single administration; 1 h before pre-exposure and conditioning) abolishes LI in male Sprague-Dawley rats receiving 0, 10, 20, or 40 stimulus pre-exposures; the vehicle control group still exhibits LI after 20 and 40 pre-exposures, whereas the SR 142948A group exhibits no LI at any pre-exposure level^[5].
SR 142948A (0.25-1 mg/kg; i.p.; single administration; 20 min before psychostimulant challenge) inhibits psychostimulant-induced hyperactivity in male CD1 mice; both 0.25 and 1 mg/kg reduce locomotor activity during the 10-60 min observation period, with 1 mg/kg completely blocking hyperactivity; 1 mg/kg alone does not alter locomotor activity^[6].
SR 142948A (1 mg/kg; i.p.; administered on days 1, 3, and 5; 20 min before conditioned stimulus) does not affect the formation of conditioned place preference (CPP) in male CD1 mice^[6].
SR 142948A (0.1 mg/kg; i.p.; single administration) does not alter electrically stimulated dopamine efflux or basal tonic dopamine efflux in the nucleus accumbens or striatum of anesthetized male Sprague-Dawley rats^[7].
SR 142948A (0.01-0.1 mg/kg; i.p.; single administration; 5 min before Haloperidol 50 μg/kg administration) enhances Haloperidol-promoted phasic electrical stimulation-induced dopamine efflux in the nucleus accumbens; Haloperidol alone increases the maximal effect by 51% compared with pre-administration, and the combination with 0.1 mg/kg SR 142948A increases it by 236%, while 0.01 mg/kg SR 142948A increases the effect by 97% at 30 min after Haloperidol administration; no clear enhancement is observed in the striatum^[7].
SR 142948A (0.1 mg/kg; i.p.; single administration; 5 min before dopaminergic pharmacological stimulation) does not significantly alter the changes in nucleus accumbens dopamine efflux induced by high-dose Haloperidol, excitatory drugs, or Nomifensine (HY-B1110), but attenuates the decrease in dopamine efflux induced by dopamine receptor agonists, reducing the maximum decrease from 55% to 30% and shortening the duration of the decrease^[7].
SR 142948A (10-100 μg/kg; i.p.; single administration; 1 h before antipsychotic administration) region-selectively modulates antipsychotic-induced Fos expression in male Sprague-Dawley rats: no significant effect in the medial prefrontal cortex, nucleus accumbens shell, and lateral septum; increases olanzapine-induced Fos-positive neurons by 38% and 57% in the dorsomedial caudate putamen; decreases haloperidol-induced Fos expression by 37% and 29% and increases olanzapine-induced Fos-positive neurons by 35% and 135% in the dorsolateral caudate putamen^[8].
SR 142948A (100 μg/kg; i.p.; single administration; 1 h before antipsychotic administration) alone does not induce significant catalepsy and does not significantly alter Haloperidol- or Clozapine (HY-14539)-related catalepsy in either the block test or the bar test; when combined with Olanzapine (HY-14541), it enhances catalepsy, with enhancement at 15 and 30 min in the block test and increased catalepsy scores at 5, 15, and 60 min in the bar test^[8].
SR 142948A (0.1-10 μM; 65 nL local administration into the ventral tegmental area; single administration; 1 min before 0.1 μM Neurotensin administration) dose-dependently inhibits neurotensin-induced dopamine efflux in the nucleus accumbens of anesthetized male Sprague-Dawley rats pretreated with pargyline; 3 and 10 μM reduce the effect by 53% and 81%, respectively, while 0.1 and 1 μM show no significant effect, and the inhibitory effects of 3 and 10 μM remain at 38% and 47%, respectively, at 16 min^[9].
SR 142948A (0.1-100 μg/kg; i.p.; single administration; 1 h before pre-exposure and conditioning) dose-dependently disrupts latent inhibition (LI) in male Sprague-Dawley rats; with 20 stimulus pre-exposures, the 0.1 and 1 μg/kg groups still retain LI, whereas the 10 and 100 μg/kg groups no longer exhibit LI; with 30 stimulus pre-exposures, none of the tested dose groups exhibit LI. None of the doses significantly affect conditioned response inhibition in non-pre-exposed rats^[5].
SR 142948A (10 μg/kg; i.p.; single administration; 1 h before pre-exposure and conditioning; Sulpiride (HY-B1019) 100 mg/kg i.p. administered 30 min before the experiment) alone disrupts 30 pre-exposure-induced LI, whereas LI is restored when combined with the dopamine D2 receptor antagonist Sulpiride; no significant treatment effect is observed in the non-pre-exposed group^[5].
SR 142948A (0.003-0.1 mg/kg; i.p.; single administration; 5 min before Haloperidol 50 μg/kg administration) dose-dependently enhances Haloperidol-induced sustained dopamine efflux in the nucleus accumbens; Haloperidol alone increases the maximal effect by 137%, and combined with 0.1 mg/kg SR 142948A it increases by 228%, while 0.003 mg/kg has no effect and 0.01 mg/kg shows a trend toward enhancement^[7].