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1.
Peptides ; 31(8): 1617-24, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20434497

ABSTRACT

Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)), a tetrapeptide present in the enzymatic digest of bovine beta-casein, is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 1-3. Two of the obtained analogs, [Dmt(1), D-Ala(2), D-1-Nal(3)]morphiceptin and [Dmt(1), D-NMeAla(2), D-1-Nal(3)]morphiceptin (Dmt-2',6'-dimethyltyrosine and d-1-Nal-3-(1-naphthyl)-D-alanine)) displayed very high mu-receptor affinity, resistance to enzymatic degradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test after intracerebroventricular but not intravenous administration, which indicated that they could not cross the blood-brain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility. We report that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception, inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome.


Subject(s)
Endorphins/chemistry , Endorphins/chemical synthesis , Endorphins/pharmacology , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Peripheral Nervous System Agents/chemical synthesis , Peripheral Nervous System Agents/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacology , Animals , Antidiarrheals/chemical synthesis , Antidiarrheals/chemistry , Antidiarrheals/metabolism , Antidiarrheals/pharmacology , Colon/drug effects , Colon/metabolism , Drug Design , Drug Stability , Endorphins/administration & dosage , Endorphins/metabolism , Female , Gastrointestinal Motility/drug effects , In Vitro Techniques , Injections, Intraperitoneal , Injections, Intraventricular , Ligands , Male , Mice , Mice, Inbred C57BL , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Neurotransmitter Agents/chemistry , Neurotransmitter Agents/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Pain Measurement , Peripheral Nerves/drug effects , Peripheral Nervous System Agents/chemistry , Peripheral Nervous System Agents/metabolism , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
2.
J Med Chem ; 48(1): 292-305, 2005 Jan 13.
Article in English | MEDLINE | ID: mdl-15634024

ABSTRACT

A series of 36 imidazopyridineacetamides (2-37) were designed and synthesized to evaluate the effects of structural changes on the amide nitrogen at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include variations in the length and number of the alkyl groups as well as introduction of different aromatic, heteroaromatic, and conformationally constrained groups. The affinities of these compounds for CBRs and PBRs were determined, and the results indicate that bulkiness of the substituents, their branching, and length beyond an optimal value may cause hindrance to the ligand in its interaction with the receptor. The presence of aromatic or conformationally constrained substituents on the carboxamide nitrogen can be conducive to high affinity and selectivity. Furthermore, the ability of a subset of the most active ligands to stimulate synthesis of neuroactive steroids in plasma and brain was evaluated in vivo and in vitro. Compound 3 exhibited very marked effects on the peripheral and central synthesis of neuroactive steroids, while 36 (potent at subnanomolar level) showed a slight ability to affect neuroactive steroid content in the cerebral cortex.


Subject(s)
Peripheral Nervous System Agents/chemistry , Peripheral Nervous System Agents/pharmacology , Receptors, GABA-A/drug effects , Steroids/biosynthesis , Structure-Activity Relationship , Acetamides/chemistry , Amides/chemistry , Animals , Biochemistry/methods , Blood/drug effects , Blood/metabolism , Brain/drug effects , Brain/metabolism , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Drug Evaluation, Preclinical/methods , Electrophysiology/methods , Female , Ligands , Male , Nitrogen/chemistry , Oocytes/drug effects , Quantitative Structure-Activity Relationship , Rats , Rats, Sprague-Dawley , Xenopus
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