Synthesis and Biological Effects of c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a New Analogue of Neurotensin that Crosses the Blood−Brain Barrier

Abstract

The central administration of neurotensin (NT) or of its C-terminal hexapeptide fragment NT(8-13), produces strong analgesic effects in tests evaluating acute pain. The use of NT-derived peptides as pharmaceutical agents to relief severe pain in patients could be of great interest. Unfortunately, peptides do not readily penetrate the blood-brain barrier. We have observed that the cyclic NT(8-13) analogue, c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012, compound 1), when peripherally administered to mice produced analgesic and hypothermic effects, suggesting the peptide penetrates the blood-brain barrier and functions effectively like a drug. Moreover, dimeric compounds show increased potency compared to their corresponding monomer. We present the synthesis of the cyclic dimer compound 1 (JMV2012). In mice, compound 1 induced a profound hypothermia and a potent analgesia, even when peripherally administered. Compound 1 appears to be an ideal lead compound for the development of bioactive NT analogues as novel analgesics drugs.

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

“…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). An advantage of the approach described here is that ANG2002 maintains the full-length sequence of NT, albeit conjugated to a single An2 molecule.…”

Opioid Glycopeptide Analgesics Derived from Endogenous Enkephalins and Endorphins

“…Contrary to the belief that small molecules with molecular weights under 400 readily cross the BBB, it has been observed that almost 98% of small molecules do not readily cross the BBB. Further, evidence has accumulated that peptides can penetrate the CNS by several different mechanisms [46–49]. These observations clearly indicate molecule size is not the primary factor, but rather the overall physiochemical characteristics of the molecule is critical for BBB transport.…”

Identification of N-[(5-{[(4-Methylphenyl)sulfonyl]amino}-3-(trifluoroacetyl)-1H-indol-1-yl)acetyl]-l-leucine (NTRC-824), a Neurotensin-like Nonpeptide Compound Selective for the Neurotensin Receptor Type 2

“…12−16 The vast majority of these compounds produce analgesia that is accompanied by hypothermia and hypotension, a feature ascribed to interaction with the NTS1 receptor. 17,18 Reports from the study of the NTS2 selective peptide NT79 ( 1b ) support this notion as it possessed activity against visceral pain but lacked the side effects described above.…”