Rating
Title	Highly potent NT[8-13] analogues that cross the blood-brain barrier : in vitro and in vivo evaluation of novel peptides with the potential for treating schizophrenia
Author	Kokko, Kyle Pentti
Date	2002
Affiliation/College	College of Graduate Studies
Department	Pharmaceutical Sciences
Extent	x, 183 leaves : ill. 29 cm
Source	QV 77.9 K79h 2002
Subject.MeSH	Academic Dissertations Neurotensin--analogs & derivatives Neurotensin--agonists Schizophrenia--drug therapy Antipsychotic Agents--pharmacology
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd2002_kokko_kp
Abstract	Since NT was hypothesized to act as an endogenous neuroleptic, studies have shown that all clinically effective neuroleptics illicit pronounced effects on the NT system. Hence, the development of NT agonist and antagonist to probe this phenomenon is of significant clinical interest. This work describes the development ofNT[8-13] analogues that incorporate non-natural homologues of arginine (Arg) and lysine (Lys) in the Arg(8) position. These analogues were designed to exhibit enhanced binding affinity through desolvation of the ionic interaction between the novel, cationically charged side-chains and neurotensin receptors (NTRs). In addition, these analogues were designed to resist peptidase degradation and facilitate transport across the blood-brain barrier (BBB). Based upon the data accumulated in this dissertation, we have identified three distinct classes of NT[8-13] analogues. Class 1 analogues possess alky l-arginines substituted for Arg in the Arg(8) position [KK16-19]. In general, these peptides bind with greater affinity to NTRs. However, these analogues are only slightly more stable to peptidase degradation in rat serum (t1l2 14-32 mins) compared to NT[8-13] (t1/2 = 5.78 min). Therefore, these analogues are useful leads to investigate the topography of NTRs. However, they lack the stability for further in vivo analysis. Class 2 analogues possess azido-acid homologues of Arg, homolysine (Hlys), Lys and ornithine (Orn) in the Arg(8) position [KKl-12 and KK15]. These peptides bind with varying affinity NTRs compared to NT. Incorporation of the azido group at the N-tenninus dramatically increased the stability of these peptides (t1l2 103-216 mins). However, none of these peptides exhibited in vivo effects when administered intraperitoneally (LP.). In addition to azido-acid homologues of Hlys and Arg substituted for Arg(8) position, Class 3 analogues possess tert-Leu substituted in the Ile(l2) position [KK13, KK14, and KK20]. These analogues bind with limited affinity (0.3-34.5%) to NTRs compared to NT. However, these analogues are completely (> 24 hrs) stable to peptidase degradation in rat serum. Therefore, these analogues are able to cross the BBB and elicit specific CNS mediated events such as induction of hypothermia. Behavioral assays indicate that KK13 is likely to mediate activities implicated in the pathophysiology of schizophrenia as indicated by its ability to inhibit d-amphetamine induced hyperlocomotion without superfluous side effects such as antinociception and induced catalepsy. This compound is considered an important lead for the development of an antipsychotic drug that would work via a novel mechanism, direct agonism of the NT system.

Highly potent NT[8-13] analogues that cross the blood-brain barrier : in vitro and in vivo evaluation of novel peptides with the potential for treating schizophrenia

Description

Tags

Comments