Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-HT receptors are subdivided into 3 families, 5-HT1, 5-HT2, and 5-HT3, of which subtypes have been described. The 5-HT receptor field has experienced over the last 10 years a revival due to the availability of new and more selective drugs and new techniques. This communication deals essentially with the biochemical approaches to characterize 5-HT1D receptors, and their comparison with 5-HT1B receptors. The methods used include radioligand binding, in vitro autoradiography, and second messenger studies. 5-HT1 receptor subtypes are labeled with [3H]5-HT and present a large heterogeneity: no less than 4 subtypes have been characterized: 5-HT1B and 5-HT1D are labeled respectively with [125I]cyanopindolol, and [3H]5-HT under appropriate conditions. Although some similarities are evident, the pharmacology of the two receptors is clearly different. Rat 5-HT1B receptors recognize with high affinity a number of beta-adrenoceptor antagonists, such as SDZ 21-009, cyanopindolol, pindolol, propranolol and isamoltane. In contrast, calf, pig or human 5-HT1D receptors show significantly lower affinities for these drugs. 5-HT1D receptors show high to intermediate affinities to compounds such as PAPP, DP-5-CT, 8-OH-DPAT, yohimbine and rauwolscine, whereas 5-HT1B receptors have very low affinities for these compounds. The presence of 5-HT1B receptors has been documented convincingly only in rat, mouse and hamster. 5-HT1D receptors have been demonstrated in pigeon, guinea-pig, cat, dog, pig, calf, monkey, and man. The distribution of 5-HT1B and 5-HT1D receptors in all species examined so far, is very similar: high concentrations of sites are found in the nigro-striatal pathway, caudate-putamen, globus pallidus and especially substantia nigra. The subicullum shows also high densities of sites. Similar functional correlates have been proposed to 5-HT1B and 5-HT1D sites. Thus, 5-HT1D receptors are negatively coupled to adenylate cyclase in guinea-pig and calf substantia nigra, and 5-HT1B receptors are negatively coupled to adenylate cyclase in rat substantia nigra. Further, it is established that terminal 5-HT autoreceptors are of the 5-HT1B type in rat cortex, and of the 5-HT1D type in guinea-pig, pig, human and possibly rabbit cortex. In the rat saphenous vein, 5-HT1B receptors mediate inhibition of noradrenaline release. Preliminary evidence suggests that the canine basilar artery and saphenous vein, described as models for "5-HT1-like" receptors, could contain 5-HT1D receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serotonin 5-HT1D receptors. 225 8

The effects of several putative 5-HT1 receptor-subtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(m-trifluoromethylphenyl)piperazine), mCPP (1-(m-chlorophenyl)piperazine), CGS 12066 (7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)- piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5-HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HT1B versus 5-HT1A selective. Quipazine showed equal potency at 5-HT1B and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? 277 Aug 89

1. A number of centrally acting hypotensive agents and other ligands with high affinity for 5-hydroxytryptamine1A (5-HT1A) recognition sites have been tested on forskolin-stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5-HT1A-receptors. 2. Concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity was elicited by the reference 5-HT1-receptor agonists (mean EC50 value, nM): 5-HT (22), 5-carboxamidotryptamine (5-CT, 3.2), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 8.6), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT, 2.3), 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (PAPP or LY 165163, 20), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). Emax amounted to 18-20% inhibition for all but the latter two agonists (14%). 3. The following hypotensive agents with high affinity for 5-HT1A sites were potent agonists in this system (mean EC50 value, nM): flesinoxan (24), indorenate (99), erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl )- 2-benzimidazolinone (R 28935, 2.5), urapidil (390) and 5-methyl-urapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60-80% efficacy. 4. Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. 5. Spiperone and methiothepin (each 1 microM) caused rightward shifts of the concentration-effect curve to 8-OH-DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 microM) and the (-)- and (+)-enantiomers of pindolol (1 microM and 0.1 mM, respectively). 6. There was an excellent correlation (r = 0.90, P = 0.0001) between the pEC50 values (ranging from 6.4 to 8.7) of the 19 agonists tested at adenylate cyclase and their pKD for 5-HT1A recognition sites. Apparent pKB values of antagonists at adenylate cyclase and their pKD values for 5-HT1A binding sites were also significantly correlated. 7. This study further indicates that the 5-HT1A recognition site and the 5-HT receptor mediating inhibition of adenylate cyclase in hippocampus are the same. The data show that a number of centrally acting hypotensive agents with high affinity for the 5-HT1,A site are potent agonists in this model, suggesting an involvement of central 5-HTIA-receptors in the control of blood pressure.
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PMID:Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus. 320 99

Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS. The diversity of serotonin actions is due to the existence of several different receptor subtypes. In this study we report the cloning of a full-length cDNA, coding for a novel serotonin receptor (5-HTap2). The receptor protein bears the characteristics of G protein-coupled receptors. It shares 68% and 34% of its amino acid sequence identity with the 5-HTlym receptor from Lymnaea stagnalis and the mammalian 5-HT1A receptor, respectively. When transfected in HEK 293 cells, 5-HTap2 was negatively coupled to adenylate cyclase. Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [3H]LSD binding was: methiothepin > metergoline > 5-CT > PAPP > 5-HT > ketanserin > NAN-190 > 8-OH-DPAT > clozapine. RT-PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells. The expression of 5-HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia. Moreover, the high expression of 5-HTap2 in the bag cells, associated with its pharmacological profile, suggests that this receptor may be implicated in modulating the afterdischarge during the egg-laying behavior.
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PMID:Functional characterization of a novel serotonin receptor (5-HTap2) expressed in the CNS of Aplysia californica. 1190 24