Opioid and Cannabinoid Receptors - Drug Design and Discovery - page 316

TABLE 19.1
Opioid Receptor Ligands

Receptor Agonist Antagonist Agonist Effect(s)

M Morphiceptin Naloxone Analgesia

DAGO Respiratory depression

Normorphine Miosis

Sufentanyl Reduced gastrointestinal motility

Nausea
Vomiting
Euphoria

Deltorphin ICI 154,126 Supraspinal analgesia

D

DPDPE ICI 174,864

DADLE

K U 50,488 MR2266 Analgesia (spinal level)

Tril uadom miosis (weak)
Respiratory depression (weak)
Dysphoria

Note: DAGO, Tyr-d-Ala-Gly-MePhe-Gly-ol; DPDPE, [d-Pen 2 , d-Pen 5 ]enkephalin; Pen,
penicillamine; DADLE, [d-Ala 2 , d-Leu 5 ]enkephalin; deltorphin II, Tyr-d-Ala-Phe-Glu-
Val-Val-Gly-NH 2 ; morphiceptin, b-casomorphin-(1-4)-amide or Tyr-Pro-Phe-Pro-NH 2 .

At that time, there were no hints of what kind of compounds to look for. After 2 years of collecting
extracts from pig brain and applying them in a functional bioassay, Kosterlitz and coworkers in 1975
identii ed two closely related endogenous pentapeptide opioids (Table 19.2).
The amino acid sequences are YGGFM and YGGFL and termed as [Met]- and [Leu]-enkephalin,
respectively. Since then, many other peptide opioids of varying lengths have been identii ed. They
are all cleavage products of longer peptides and can be divided into four families based on their
precursors. Three of these families all start with the [Met]- and [Leu]-enkephalin. The endogenous
opioid peptides have varying afi nities for the opioid receptor subtypes; however, none of them
are specii c for a single subtype, although the neuropeptide nociceptin is the endogenous ligand
specii c for ORL 1 . The precursors are often made up of repeating copies of the opioid peptide
products.
High afi nity opioid receptor peptides (dermorphins and deltorphins) have been isolated from
frog skins and are quite unusual in having d-amino acids in the sequence. Also milk-derived
casomorphins, hemorphins from hemoglobin, and cytochrophins (fragments of cytochrome B),
have low afi nity for the opioid receptors.
Besides the endogenous peptides, it has been shown that morphine is present in various tissues
and body l uids and SH-SY5Y human neuroblastoma cells are capable of producing morphine. The
biosynthetic route is similar to that found in Papaver somniferum .

19.1.3 N ONENDOGENOUS O PIOID R ECEPTOR L IGANDS
The synthetic efforts in the opioid i eld over the last century have mainly been stimulated by the
search for a safer alternative to morphine that maintained the analgesic effects but was devoid of
respiratory depression and abuse potential. Different medicinal chemistry approaches have been
followed in the development of opioid receptor ligands: