Opioid message

The best-understood sites of action of morphine are at spinal and brainstem/ midbrain loci, producing both the wanted and unwanted effects of the opioid. The spinal actions of opioids and their mechanisms of analgesia involve (1) reduced transmitter release from nociceptive C-fibres so that spinal neurons are less excited by incoming painful messages, and (2) postsynaptic inhibitions of neurons conveying information from the spinal cord to the brain. This dual action of opioids can result in a... 

Portoghese PS, Sultana M, Nagase H, Takemori AE. Application of the message-address concept in the design of highly potent and selective nonpeptide 6 opioid receptor antagonists. J Med Chem 1988 31 281-282. 

Rational design of nonpeptide 5 opioid ligands - the message address concept... 

Dores RM, Akil H, Watson SJ. Strategies for studying opioid peptide regulation at the gene, message and protein levels. Peptides 1984 5(suppl 1) 9—17. 

Chavkin and Goldstein [3] pointed out that endogenous opioid peptides conform to a message-address motif, and it was suggested that the invariant tetrapeptide sequence Tyr-Gly-Gly-Phe can be viewed as the message while subsequent amino acid residues constitute the address. A modification of this... 

Figure 3 An approach to the design of a nonpeptide, delta-selective opioid antagonist based on the message-address concept. The message and address components of the delta-selective peptide enkephalin (upper) are compared to those in an opiate (lower).

The opioid peptides can be viewed to contain two elements an essential message component that is recognized by a homologous receptor subsite... 

The incorporation of glycosides into peptide neurotransmitters imparts drug-like character to the neurotransmitter message via membrane hopping . The importance of the gly-copeptide-membrane interaction is emphasized, and the biousian theory is briefly explained. Application of this approach to enkephalins, the endogenous opioid peptides, leads to potent analgesic compounds capable of systemic delivery. The clinical applications of these compounds are advocated by the author. 

Recently, a new class of opioid peptides, the endomorphins (52 and 53, Fig. 7.9), were discovered (264) that do not share the classical "message" sequence with other mammalian opioid peptides. In contrast to other mammalian opioid peptides, the endomorphins show high selectivity for their preferential receptor, the receptor (Table 7.9). Since their discovery the pharmacology of these new mammalian opioid peptides has been studied extensively (see Ref 265 for a detailed review). 

Fig. 13 Message-Address Concept proposed for opioid antagonists. Reprinted from [28] with permission from Elsevier. Copyright (2008)...

To design a new agonist, we first attempted to remove the accessory site of nor-BNI and maintain the message and address sites. The message site of nor-BNI, a 4,5-epoxymorphinan skeleton with a cyclopropylmethyl substituent, was considered to be indispensable for opioid activity because it corresponded to the tyrosine of endogenous opioid peptides. Therefore, we postulated that the accessory site of nor-BNI was located in the address subsite of this antagonist. 

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