NT79: A novel neurotensin analog with selective behavioral effects

Abstract

Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin, but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79 which exhibits selective behavioral effects.NT79 was tested in animal models for pain (thermal -hot plate test; visceral -acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphineinduced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79.Binding data at molecularly-cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED 50 of 0.14μg/kg, while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, damphetamine-induced hyperactivity, and reducing d-amphetamine-and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.

Spinal NTS2 receptor activation reverses signs of neuropathic pain

“…Likewise, intrathecal or intrarostroventral medullary administration of both NTS2 analogs ß-lactotensin and levocabastine induced analgesia in rats, as measured in the tail-flick test (20,26,70,71). Finally, the NT79 compound, which exhibits higher selectivity to NTS2, also attenuated both formalin-induced nociceptive behaviors and acetic acid-induced writhing responses (17, 27,72). In line with our previovis findings demonstrating that NTSl agonists produced potent antiallodynic effects in nerve-injured rats (21), we can thus conclude that the recruitment of both NTSl and NTS2 receptors mediates the analgesic actions of NT in chronic neuropathic pain conditions.…”

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

“…Likewise, PD149163, a reduced-amide NT [8][9][10][11][12][13] , showed improved metabolic stability after systemic administration and maintained the analgesic activities of the native NT peptide (65)(66)(67). Subsequently, several additional systemically infused but centrally acting analogs (i.e., NT66L, NT69L, NT79, and ABS212) were synthesized by combining N-terminal modifications and incorporation of non-natural amino acids at positions 8, 9, 11, and 12 (63,64,(68)(69)(70)(71). Finally, in compound JMV2012, the unmodified NT 8-13 fragment has been dimerized and cyclized (72).…”

Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

“…In addition, the NTS2 selective agonist NT79 was shown to block amphetamine-mediated hyperactivity like NTS1 agonists (Boules et al, 2010). These studies suggest that NTS2 may also inhibit dopamine signaling (Figure 2A).…”