Opioid analgesics structure-activity relationships

The focus of this chapter is on recent developments in the opioid field, with summaries of key features of the structure-activity relationships (SAR) of older compounds. Much of the early opioid SAR is discussed in detail in two comprehensive books on opioid analgesics published in 1986 (12, 13). Specific areas in which there has been considerable research in the last decade and which are discussed in this chapter include the molecular biology of opioid receptors (see Section 3.2.4), the design... 

Halfpenny PR, Horwell DC, Hughes J, Hunter JC, Rees DC (1990) Highly selective K-opioid analgesics. 3. Synthesis and structure-activity relationships of novel N-[2-(l-pyrrolidinyl)-4-or -5-substituted cyclohexyl]arylacetamide derivatives. J Med Chem 33 286-291... 

Structure-Activity-Relationships of Non-Peptide Kappa-Opioid Analgesics A Perspective of the Last 10 Years... 

Structure-activity relationships of non-peptide kappa-opioid analgesics a perspective of the last 10 years... 

Clark CR, Halfpenny PR, HIM RG, et al. Highly selective k opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-amlnocyclohexyl)aryl]acetamlde and N-[(2-amlnocyclohexyl)aryloxy]acetamlde derivatives. J Med Chem 1988 31 831-836. 

The pyrrolidine indole alkaloids (-n)-chimonanthine, weso-chimonanthine, and psychotridine also showed analgesic activity [120, 121], but the P. colorata quinoline alkaloids did not present positive results to the nociceptive tests, suggesting strong structure-activity relationship [115]. Capsaicin (the active component in pepper)-induced pain models suggest alkaloid action on opioid and glutamate receptors [119-121]. 

While morphine is constrained to be phenyl axial, it is clear that compounds that are constrained to be phenyl equatorial, such as the phenylmorphans (Figure I), are also capable of potent analgesic activity. These compounds predominantly interact with p-receptors, as does phenyl axial morphine. To account for the diverse structures that can produce opioid analgesia, a pharmacophore model than can accommodate both phenyl axial and phenyl equatorial compounds was proposed. This model is best illustrated by a- and P-azabicyclanes (Figure 4), which are constrained to be phenyl axial and phenyl equatorial, respectively. Despite this structural difference, a-and P-azabicyclanes have similar analgesic potencies and similar structure-activity relationships. The key feature of the... 

Influencing the efficacy or potency of chemicals is a strategy used by the pharmaceutical industry as part of the drug discovery process that can be incorporated into designing safer industrial chemicals. Efficacy is the maximal effect, either therapeutic or toxic, that a chemical can achieve. Potency is a measure of the amount of a substance that is needed to attain a given response level. Opioid analgesics are examples of where structural modifications have been used to establish a relationship between structure and activity. ... 

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