Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8-13) analogues containing non-natural arginine and lysine residues.
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 NTR(1), 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.
Hadden
M Kyle
MK
Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, PO Box 250140, Charleston, SC 29425, USA.
Orwig
Kevin S
KS
Kokko
Kyle P
KP
Mazella
Jean
J
Dix
Thomas A
TA
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001120:Arginine / Q000737:chemistry*; D001682:Biological Availability; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008239:Lysine / Q000737:chemistry*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000187:drug effects
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C054381:neurotensin (8-13); D001120:Arginine; D006220:Haloperidol; D008239:Lysine; D003913:Dextroamphetamine