neurotensin and Pain

Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH

Topics: Amino Acid Sequence; Animals; Disease Models, Animal; Drug Design; Humans; Male; Mice; Oligopeptides; Pain; Peptides; Protein Binding; Receptors, Neurotensin; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship

Compounds acting via the neurotensin receptor type 2 (NTS2) are known to be active in animal models of acute and chronic pain. To identify novel NTS2 selective analgesics, we searched for NTS2 selective nonpeptide compounds using a FLIPR assay and identified the title compound (NTRC-824, 5) that, to our knowledge, is the first nonpeptide that is selective for NTS2 versus NTS1 and behaves like the endogenous ligand neurotensin in the functional assay.

Topics: Analgesics; Animals; Binding, Competitive; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Humans; Kinetics; Leucine; Models, Chemical; Molecular Structure; Pain; Rats; Receptors, Neurotensin; Sulfonamides

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.

Topics: Amino Acid Sequence; Analgesia; Analgesics; Animals; Blood-Brain Barrier; Body Temperature; Dose-Response Relationship, Drug; Humans; Hypothermia; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Mice; Neurotensin; Oligopeptides; Pain; Pain Measurement; Peptides, Cyclic; Receptors, Neurotensin

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship