کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8998186 1115607 2005 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8-13) analogues containing non-natural arginine and lysine residues
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8-13) analogues containing non-natural arginine and lysine residues
چکیده انگلیسی
Neurotensin (NT) and its active fragment NT(8-13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently, our laboratory designed and studied a first-generation NT(8-13) derivative, KK13, that elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT(8-13) analogues (KH1-KH30) studied in this paper. Initial screening of these analogues for CNS activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28-KH30) that warranted further investigation. Each compound maintained binding affinity for NTR1, however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analogue; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated d-amphetamine induced hyperlocomotion, a hallmark of current clinically effective antipsychotic drugs, after both IP and oral administration. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of d-amphetamine induced hyperlocomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 49, Issue 8, December 2005, Pages 1149-1159
نویسندگان
, , , , ,