Receptor multiplicity

Fig 10 1 The agonist activities of various compounds in the mouse vas deferens and guinea pig ileum and their potencies to inhibit 3H-Leu-enkephalm and [3H]naloxone binding in homogenates of guinea pig brain (pH 7 4 at 0°C, no Na+, 150 min) The numbers on the absiccsa indicate the amino acid sequence of /3 -lipoprotein, Leu, leu-enkephalin and Mo, morphine All peptides are synthetic (61-91, ovine /3-endorphin, 61-65, met-enkephahn and leu-enkephalin) 

Since the rank orders of activity in relation to analgesic potency in man and inhibition of the contraction of the GPI concurred for morphine, normor-phine, and a wide range of synthetic opioids,(96) it was concluded that the / -receptors must be associated with analgesia. The role of 8- and other putative receptors is uncertain and is the subject of much speculation.(97) 

In a later paper(98) activity patterns were characterized by the ratio of GPI to MVD potencies and by the ratio of potency in inhibiting H-naloxone 

The work of Vaught et a/., 215) in which natural enkephalins are shown to have much lower affinities for /x-sites than generally believed, and evidence presented of Leu-enkephalin potentiating and Met-enkephalin attenuating morphine analgesia in mice are discussed in Chapter 13 (p. 490). 

Other peptides with S-selectivity have also been reported (e.g., the hep-tapeptide[ Arg6, Phe7]-Met-enkephalin present in rat, bovine, and human brain in amounts comparable with those of Leu-enkephalin). 103) Among the most specific so far described is a dimeric tetrapeptide amide in which the monomer units (Tyr-D-Ala-Gly-Phe-NH) are linked by a 12-carbon chain. 104) The monomer itself shows /x-selectivity, but this changes to a preference for 5-receptors when two units are linked by a bimethylene chain 5-seleclivity increases as the length of the chain link increases and shows a dramatic rise when a 10-chain is replaced by a 12-chain link (Table 10.4). The dimer DTE12 

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Hata AN, Breyer RM (2004) Pharmacology and signaling of prostaglandin receptors Multiple roles in inflammation and immune modulation. Pharmacol Ther 103 147-166... 

Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW. Kappa opiate receptor multiplicity evidence for two U50,488-sensitive k3 subtypes and a novel k3 subtype. J Pharmacol Exp Ther 1989 251 461-468. 

Simon EJ, Gioannini TL. Opioid receptor multiplicity isolation, purification and chemical characterization of binding sites. In Opioids I. Handbook of Experimental Pharmacology. Vol. 104 (Herz A, ed). Springer, Heidelberg, 1993 3-26. 

This confusion is complicated even further by receptor multiplicity. Consider, for example, the presence of opiate receptors in both the central nervous system and the ileum. Not only do they have different roles as participants in neuromodulation and peristaltic... 

Receptor plasticity could be invoked as the underlying common trait of multiple receptors. For example, although the multiple adrenergic isoreceptors are similar, they react to the common neurotransmitter norepinephrine (2.4) in a quantitatively different manner. They also show a drug specificity that varies from organ to organ and differs in various species of animals. In subsequent chapters of this book, receptor multiplicity as the rule rather than the exception will become amply evident. It is to be hoped that, in time, the comparison of isoreceptor molecular structures will provide precise criteria for their differentiation. 

Dennies, T.B., Fournier, A., St. Pierre, S., Quirion, R Structure activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity, J. Pharmacol. Exp. Ther. 1989, 251, 718-725. 

In Figure I, the platelet is shown to have multiple surface receptors, multiple organelles, and biochemical pathways that facilitate its communication and interaction with the... 

Chang K-J. Opioid receptors multiplicity and sequelae of ligand-receptor interactions. In ConnM, ed. The Receptors. New York Academic Press, 1984 1-81. 

Figure 5.1. Types of potassium channels. Leak channels have four transmembrane helices per subunit, voltage-gated channels (Ky) have 6, and inward-rectifier channels (K. ) have two. The activity of Ky channels is modulated by accessoiy proteins such as KCR-1 and MinK, whereas Kj. channels are controlled by the sulfonylurea receptor. Multiple subtypes exist for all types of channels.

As macrocyclic chemistry has developed, the variety and scope of the applications of these molecules have continued to multiply. This concluding section is an attempt to provide an overview of only three of the applications of synthetic macrocycles. A particularly insightful treatment can be found in the Nobel Lecture of Jean-Marie Lehn, which describes the concept of supramolecular chemistry from simple recognition, to cation and anion receptors, multiple recognition, catalysis, transport, and molecular devices. 

Lazar MA. Thyroid hormone receptors Multiple forms, multiple possibilities. Endocrine Rev 1993 14 184-93. 

Other potential therapeutic indications of opioid morphinans include addiction, depression, feeding behavior, and Parkinson-induced tardive dyskinesia [12, 16, 18, 30-32]. Also, important research tools to investigate opioid receptor multiplicity and function in vitro and in vivo have come from the development of morphinans, including opioid antagonists cyprodime (p) [33], naltrindole (8) [34], and norbinaltorphimine (k) [35] (Fig. 2). 

M. A. Lazar Thyroid hormone receptors multiple forms, multiple possibilities. Endocrine Review 14,184 (1993). 

Autophosphorylation of the insulin receptor leads to phosphorylation of insulin receptor substrate (IRS). IRS comes in four different forms (IRS-1, IRS-2, IRS-3 and IRS-4). In muscle tissue, IRS-1 is the most important form for mediating insulin-signal transduction and lRS-1 impairment has been observed in muscle tissue of humans with DM-2 (Glund and Zierath, 2005). lRS-1 has many tyrosine phosphorylation sites. When these sites are phosphorylated by the insulin receptor, multiple insulin signals are enabled (Sun et al., 1993). IRS-1 also has several serine phosphorylation sites phosphorylation of serine residue 1101 results in inhibition of insulin signalling and provides a possible mechanism for IR (Li et al., 2004). After IRS is phosphorylated, it recruits and activates phosphatidylinositol 3-kinase (PI3-kinase). PI3-kinase phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to... 

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