Antagonists neurotensin

B HMPPA-pMeBHA PAL (TFA) astressin endothelin B antagonist neurotensin and somatastatin analogues Fmoc Adpoc/OPp tBu [394]... 

The smallest sequence possessing most of the neurotensin spectmm of activities and its high potency is the hexapeptide C-terminus (1). [D-Trp ]-Neurotensin acts like a neurotensin antagonist in perfused heart preparations, but acts like a full agonist in guinea pig atria and rat stomach strips (122). 

Kitabgi P (2002) Targeting neurotensin receptors with agonists and antagonists for therapeutic purposes. Curr Opin Drug Discov Devel 5 764—776... 

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

Neurotensin (NT) is a tridecapeptide (Table 4.2) first isolated from brain and gut by Carraway and Leeman [75] and reported by them to induce a rapid and transient hypotension, a cutaneous vasodilatation, and a cyanosis of the extremities in the anaesthetized rat. This report, along with others [76-78] indicating that the NT-induced hypotension and increased vascular permeability could be blocked by histamine receptor antagonists such as mepy-ramine [77] or by pretreatment with compound 48/80 [76], suggested that endogenous histamine (perhaps released from tissue mast cells) was involved in producing some of the biological effects of NT [78]. 

Meclinertant Antagonist of central and peripheral neurotensin receptors Blocks some central and peripheral (vasodilator) actions of neurotensin None identified... 

Neurotensin receptors can be blocked with the nonpeptide antagonists SR142948A and SR48692. SR142948A is a potent antagonist of the hypothermia and analgesia produced by centrally administered neurotensin. It also blocks the cardiovascular effects of systemic neurotensin. 

Like presynaptic dopamine autoreceptors, presynaptic histamine autoreceptors are activated by the released endogenous transmitter to inhibit further histamine release, as shown by the increase in histamine release caused by antagonists at H3 receptors a definite piece of physiology. Evidence has been presented recently that cardiac postganglionic sympathetic neurons of the guinea pig synthesize and release histamine as a co-transmitter (Li et al. 2003 2006). These noradrenaline-histamine neurons possess H3 autoreceptors which, when activated, depress the release of both noradrenaline and histamine - unlike the D2-like autoreceptors of dopamine-neurotensin neurons which modulate the release of the two cotransmitters in opposite direction (see Section 2.2). It would be of interest to see whether, conversely, activation of ot2-autoreceptors inhibits the release of histamine in the guinea pig heart. 

This theoretical receptor that considers neurotensin as part of the DA receptor accommodates DA agonists and antagonists of diverse structure (116). It Is suited to the dopaminergic 3-ben-zazepines, but it is not predictive of enantioselectivity. 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

Neurotensin-induced adrenal chromaffin cell catecholamine secretion] NEUT-R antagonist (CPA) [inhibits mast cell Histamine release]... 

At least two receptors have been cloned. These include NTSl (NTR-1 NTl high-affinity neurotensin receptor) at which the synthetic peptide analogue JMV449 is selective, and nts2 (where the functional relevance is yet to be elucidated) and here levocabastine, a histamine H] receptor antagonist, has a reasonably high affinity. 

Gully. D. et at. (1993) Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc. Natl. Acad. 

Dubuc. 1. et al. (1994) The nonpeptide neurotensin antagonist, SR 48692, used as a tool to reveal putative neurotensin receptor subtypes. Br. J. Pharmacol.. 112, 352-354. 

Gully. D. era/. (1995) Neuropharmacological profile of non-peptide neurotensin antagonists. Fundam. Clin. Pharmacol.. 9.513-521. 

SR 48527 is a qulnolinylpyrazolyl compound, a nonpeptide neurotensin receptor antagonist. It is used as a pharmacological tool. 

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