Endogenous ligand

Dmg receptors represent another type of receptor family. The central nervous system (CNS) effects of the anxiolytic, diazepam, and the psychotropic actions of the caimabiaoids and phencycUdine have resulted ia the identification of specific receptors for these molecules. This has resulted ia the search for an endogenous ligand for these receptors. Thus, ia these situations, the pharmacological action has preceded the discovery of the receptor which, ia turn, has provided clues ia several iastances to the endogenous ligand. 

The PBRis distinct from the central BZ receptor although both can be present in the same tissues in differing ratios. PBRs are predominately localized on the outer mitochondrial membrane and are thus intracellular BZ recognition sites. The PBR is composed of three subunits an 18,000 mol wt subunit that binds isoquinoline carboxamide derivatives a 30,000 mol wt subunit that binds BZs and a 32,000 mol wt voltage-dependent anion channel subunit. The porphyrins may be endogenous ligands for the PBR. PBRs are involved in the control of cell proliferation and differentiation and steroidogenesis. 

The primary endogenous ligand for RARs is trans- Js. RA is the endogenous ligand for RXRs. Rol3-7410 (278) and Ro 41-5253 (279) are... 

Dihydroxyvitamin (283) is the endogenous ligand for the vitamin receptor (VDR). It modulates genomic function in a tissue and developmentaHy specific manner and affects ceU proliferation, differentiation, and mineral homeostasis (74). Vitamin mobilizes calcium from the bone to maintain plasma Ca " levels. Vitamin and VDR are present in the CNS where they may play a role in regulating Ca " homeostasis. Vitamin D has potent immunomodulatory activity in vivo. 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

Indications fliat endogenous AHR hgand(s) may be derived from tryptophan have been reported repeatedly (87JBC15422 91MI5 98MI6 OOMIl 1). This implies fliat the tryptophan photoproduct 202 and molecules with a similar sbuctural framework are the most likely candidates as endogenous ligands for the AHR. 

FIGURE 7.2 Model of LFA-1 showing the binding domain of ICAM-1 (the endogenous ligand for this protein) and the binding site for lovastatin, an allosteric modulator for this protein. Redrawn from [7],... 

Orphan receptor, a gene product that is predicted to be a receptor through structure and spontaneous interaction with G-proteins but for which there is no known endogenous ligand or physiological function. 

Subtype, often refers to a receptor and denotes a variation in the gene product such that the endogenous ligand is the same (i.e., neurotransmitter, hormone) but the function, distribution, and sensitivity of the receptor subtypes differ. Antagonists often can distinguish receptor subtypes. 

Receptor Endogenous ligands Main tissue distribution Signalling Main biological effects... 

Nociceptin is an opioid peptide, which is the endogenous ligand for the opioid receptor-like protein (ORL). 

Endogenous ligand Endomorphin-1,-2 Met/leu-enkephalin Dynorphin A Nociceptin/OFQ... 

Natural PPARy Ligands. Endogenous ligands demonstrated to bind and activate PPARy in vitro include unsaturated fatty acids and their derivatives such as prostaglandin J2 (15-deoxy-A12,l4-PGJ2). Consistent... 

PPAR isotype Tissues of highest expression Primary physiological effects Endogenous ligands Synthetic ligands Associated disease state/ indication... 

CICR is modulated by several endogenous ligands. Mg2+ inhibits CICR by acting as a competitive... 

Synthetic molecule or peptide that is able to activate an orphan receptor but differs in chemical structure from the natural endogenous ligand... 

Trypsin is a major proteolytic digestive enzyme and the identified endogenous ligand for proteinase-activated receptor 2 (PAR 2). 

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