Opioids lead compounds

A Double Decarboxylation Reaction of an Oxazolidinone and a Carboxylic Acid Its Application to the Synthesis of a New Opioid Lead Compound [45]... 

The main objective of this experiment was to demonstrate that a peptide lead compound could be used in rational design of a non-peptide library. One of the natural opiates, met-enkephalin, is used as a hypothetical lead compound. The averaged frequency distribution based on four SA runs is obtained (data not shown). Based on this result, 03 had the highest frequency, and the frequencies of A4, Dll, D13, D14, D16, D2, D3, D5, and D9 are also above random expectation. Apparently, 03 appeared in all the reported active peptoids with opioid activity (cf. Table 1). Comparison of the structure of met-enkephalin (Fig. 5) with 03 indicated that 03 is similar to the side chain of tyrosine, which is the N-terminal residue of met-enkephalin. Among other building blocks found more frequently than random expectation, A4, D3, and D13 are present in the reported opioid peptoids (cf. Table 1). Thus, the SA sampling correctly identified four... 

In 1997 Alan Cameron, formerly with Eastman Kodak Company of Rochester, New York, and SynPhar Laboratories, Inc., of Edmonton, Alberta, joined BioChem Therapeutic, Inc., Laval, Quebec. He has been involved at BioChem in new compound identification and optimization of existing lead compounds directed toward various therapeutic agents including antithrombotics, opioid analgesics, and anticancer and antiviral compounds. He obtained his Ph.D. under the supervision of Mike Baird and Vedene Smith at Queen s University and was a postdoctoral fellow with Mike Zerner at Florida. 

The identification of the opioid peptides in the mid-1970s opened up a whole new area for the development of opioid receptor ligands. The endogenous opioid peptides, both mammalian and amphibian (see below), have served as lead compounds that have been extensively modified to enhance potency, receptor type selectivity, stability, and/or decrease conformational flexibility. Peptide ligands selective for both fx and d opioid receptors are found in more than one type of peptide sequence. Thus some enkephalin analogs, as well as the recently discovered endomorphins, analogs of... 

The unique feature of these amphibian skin opioid peptides is the sequence between the important aromatic residues. In contrast to the enkephalins and other mammalian opioid peptides that contain the Gly-Gly dipeptide sequence between Tyr and Phe, the amphibian opioid peptides contain a single D-aminoacid (see Fig. 7.41), which apparently arises from a post-translational conversion of the L-amino acid to its d isomer (665). The identification of these unusual opioid peptides expanded our understanding of the structural requirements for interaction with opioid receptors and provided new lead compounds for further modification (see Sections 6.5.1 and... 

Researchers from the Banyu Tsukuba Research Institute reported the first nonpeptide antagonist for ORLl receptors (1037). Starting from a lead (269) from their chemical library, which again exhibited reasonable affinity but poor selectivity for ORLl receptors, these researchers identified J-113397 (270), which exhibits high affinity (K = 1.8 nM) and high selectivity for ORLl receptors over opioid receptors (1037-1039). This compound is an antagonist of OFQ/N in uitro and in vivo after subcutaneous administration (1038,1039). A series of 4-aminoquinolines (271) has also been examined for antagonist activity, based on the weak affinity of the lead compound... 

Opiates, narcotic compounds extracted or derived from opium, are a remarkable source of lead compounds for their potent pharmaceutical effects such as analgesics, antitussives and ataractics, and of which many synthetic derivatives have been prepared [8, 72], Apomorphine (28), a dopamine agonist derivative from morphine (5) but without analgesic properties like morphine, was recently approved as a therapy for Parkinson s disease [73], Hydrocodone (30) is a narcotic agent derived from thebaine (29) and is commonly combined with other analgesics such as acetaminophen and ibuprofen as drugs to relieve pain. [74]. Naloxone (31) and naltrexone (32) are both opioid receptor antagonists. Naloxone is used as a treatment for opioid... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

The use of structurally rigid DKPs as bioactive models for opioid receptor antagonists has been proposed. These compounds are used in the elucidation of the binding requirements and will lead to the design of highly selective molecules with potential clinical application for diseases of the opioid system. These include the treatment of autism, alcohol dependency, and modulation of immunity Further studies by Baures has... 

One of the more benign ancillary activities of morphine lies in its activity in suppressing the cough reflex. Catalytic reduction of codeine (1-2) leads to the dihydro derivative (4-1). Oppenauer oxidation of the hydroxyl group leads to hydrocodone (4-2) [3], a compound used extensively in cough remedies it is of note, however, that this drug retains considerable opioid activity. 

Similar to opioids, the cannabinoid system appears to be intricately involved in normal physiology, specifically in the control of movement, formation of memories, and appetite control. Basic research has discovered that members of this family of compounds have the capacity to protect threatened neurons, thereby slowing neurodegenerative processes that ultimately lead to physical disability. As the function of the physiological role of endocannabinoids becomes clearer, it appears the system may be involved in the pathology of several neurological diseases, specifically multiple sclerosis, spasticity, and pain. In 1999 the German journal, Forschende Komplementar-medizin und Klassische Naturheilkunde (Research in Complementary and Classical Natural Medicine) commented ... 

---