Subtypes

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

Adenosine receptors are members of the P purinoceptor GPCR family and can be classified into four subtypes A, 3 ... 

ATP receptors, initially classified as P2 and P2Y subtypes, have evolved into a number of subclasses including 2lj/ 2N 2D ... 

The ANP leceptoi exists in two forms, ANP and ANPg, both of which have been cloned. These membrane-bound guanylate cyclases have a single transmembrane domain, an intracellular protein kinase-like domain, and a catalytic cyclase domain, activation of which results in the accumulation of cychc guanosine monophosphate (cGMP). A third receptor subtype (ANP ) has been identified that does not have intrinsic guanylate cyclase activity and may play a role in the clearance of ANP. 

At low (1—10 nAf) concentrations ANP activates ANP whereas ANPg appears to be the physiological receptor for CNP. ANP and BNP are inactive at the latter subtype except at high micromolar concentrations. AP 811 [124833 5-OJ C gHggN 20g (58) is a selective ANP ligand. (L-a-Aminosuberic is an ANP antagonist. 

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

Two CCK receptor subtypes, CCK and CCKg are known. A related receptor, the gastrin receptor, has also been described. CCK receptors predominate in the gastrointestinal tract and pancreas and are also localized in discrete brain regions. CCKg receptors predominate in the brain. A 71623... 

Two ET GPCR subtypes, ET and ETg, have been cloned from human tissues. Both leceptois utilize IP /DAG for transduction. ET-1 and ET-2 have similai affinities for the ET subtype, whereas the affinity of ET-3 is much lower. All three peptides have similat affinities for the ETg subtype. Both receptor subtypes ate widely distributed, but ET receptors are more abundant in human heart, whereas ETg receptors constitute 70% of the ET receptors found in kidney. BQ 123 [136553-81 -6] cyclo-[D-Asp-Pro-D-Val-Leu-D-Trp], and ER 139317 (136) are selective ET antagonists. 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

The prostanoids produce effects via five main subclasses of GPCR DP, EP, FP, IP, and TP (63). The EP receptor exists ia four subtypes,... 

DOI (294) and a-methyl-5-HT (295) are selective 5-HT2 receptor agonists. Ketansetin (296) and ritansetin (297) are potent and selective 5-HT2 antagonists. SB 200646 (298) is an antagonist which has greater selectivity toward 5-HT2g and receptors compared to the 5-HT2 subtype. 

Seghtide readily distinguishes SSTR with picomolar affinity. This compound has nanomolar affinity for SSTR2 and is much weaker at the other subtypes. Ocreotide binds to SSTR, SSTR2 and SSTR receptor types. BIM 23052 [133073-82-2] D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2, and BIM 23056 [150155-61-6], (326) differentiate the SSTR and SSTR2 subtypes. NC4 28B [150155-58-1] (327) and CGP 23996 [86170-12-9] f(Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser-Asn), are SSTR agonists. L 362855 [81710-71-6] (Ala-Phe-Trp-D-Trp-Lys-Thr-Phe), is a... 

Three tachykinin GPCRs, NK, NK, and NK, have been identified and cloned. AH are coupled to phosphatidjhnositol hydrolysis. The NK receptor is selective for substance P (SP) and is relatively abundant in the brain, spinal cord, and peripheral tissues. The NK receptor is selective for NKA and is present in the gastrointestinal tract, urinary bladder, and adrenal gland but is low or absent in the CNS. The NIC receptor is selective for NKB and is present in low amounts in the gastrointestinal tract and urinary bladder, but is abundant in some areas of the CNS, ie, the spinal dorsal bom, soUtary nucleus, and laminae IV and V of the cortex with moderate amounts in the interpeduncular nucleus. Mismatches in the distribution of the tachykinins and tachykinin receptors suggest the possibility of additional tachykinin receptor subtypes. 

The effects of VIP and PACAP are mediated by three GPCR subtypes, VIP, VIP2, and PACAP receptor, coupled to the activation of adenjiate cyclase (54). The VIP subtype is localized ia the lung, Hver, and iatestiae, and the cortex, hippocampus, and olfactory bulb ia the CNS. The VIP2 receptor is most abundant ia the CNS, ia particular ia the thalamus, hippocampus, hypothalamus, and suprachiasmatic nucleus. PACAP receptors have a wide distribution ia the CNS with highest levels ia the olfactory bulb, the dentate gyms, and the cerebellum (84). The receptor is also present ia the pituitary. The VIP and PACAP receptors have been cloned. 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Two different types of P-adrenoceptors have been characterized and categorized as P - and P2-subtypes. The P -receptors are associated primarily with the cardiac muscle, whereas the P2-subtype is located peripherally. Selective P -blockers include practolol (121) and (122), atenolol (123) and (124), and betaxolol (125) and (126). 

Acetyl choline is the natural neurotransmitter for the cholinergic receptor. Two distinct receptor subtypes have been characterized based on their binding affinity for either nicotine (189) and (190) or muscarine (191). 

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