Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Vanilloid (Capsaicin) Receptors and Mechanisms

Spinopetal pathways may be activated by a variety of brainstem manipulations including microinjections of morphine which are known to modulate spinal nociceptive processing. Based on the ability of these manipulations to release spinal noradrenalin; the ability to reverse the antinociceptive effects by intrathecal adrenergic antagonists and the fact that intrathecal injections of noradrenalin mimic the antinociceptive effect, it appears that the descending modulation may be mediated by descending noradrenergic systems. Examination of the spinal receptor systems with intrathecally administered agents indicates that spinal alpha, but not beta adrenergic receptor agonists produce a powerful analgesia as measured on a variety of reflex and operant measures in mouse, rat, cat, primate and man. On the basis of agonist and antagonist structure-activity relationships it appears that a significant effect can be produced in the absence of any detectable effect on motor function by the occupation of spinal receptors. Distinguishable alpha 1 receptors also appear “analgetically-coupled,” but their effects are uniformly contaminated by signs of cutaneous hyperreflexia at doses required to produce analgesia. The ordering of potency with which intrathecal adrenergic antagonists reverse the effects of intrathecal noradrenalin is indistinguishable from that of the reversal by these intrathecal agents of the antinociceptive effects evoked by brainstem morphine. This suggests that the population of spinal receptors acted upon by exogenously administered adrenergic agonists and endogenously released noradrenalin have indistinguishable characteristics.

Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing.

Noradrenergic pain modulation.

Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper.

https://escholarship.org/content/qt8xh0s7nf/qt8xh0s7nf.pdf?t=oyg19p

Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

The effects of mu and kappa-opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side-effects in man These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion The mu-receptor agonists tested produced opiate side-effects in the mouse at doses between 24 and 34 times higher than their antinociceptive doses in the abdominal constriction test Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency In contrast, the kappa-receptor agonists only produced opiate side-effects at doses between 29 and greater than 2500 times higher than their antinociceptive doses There was no correlation between the potency ratios in these tests and in the abdominal constriction test It is concluded that mu-receptor agonists may produce both their antinociceptive effects and opiate side-effects by interacting with the mu-receptor The kappa-receptor agonists have previously been shown to produce antinociception via the kappa-receptor, but the opiate-like side-effects which appear with some of the drugs at much higher doses are probably due either to interaction with the mu-receptor or to some other non-specific action

/pdf/determination-of-receptors-that-mediate-opiate-side-effects-2rtb0atbqc.pdf

Ann G. Hayes

Papers

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

Determination of receptors that mediate opiate side effects in the mouse

The effects of a series of capsaicin analogues on nociception and body temperature in the rat

Antinociceptive activity of clonidine in the mouse, rat and dog.

Effects of single doses of capsaicin on nociceptive thresholds in the rodent