Summary
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1)
The possibility was explored that the recently defined 5-HT1D binding sites could be negatively coupled to adenylate cyclase in calf substantia nigra.
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2)
5-HT inhibited forskolin-stimulated adenylate cyclase activity in a concentration-dependent manner (EC50 valu e = 24.0 nmol/l, E max = 22.7% inhibition) in the presence of GTP (10 μmol/l), which was required for this inhibitory effect.
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3)
The following 5-HT receptor agonists inhibited adenylate cyclase activity (in decreasing order of potency): 5-carboxamidotryptamine > 5-HT > 5-methoxytryptamine > 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969) ≥ N1N-dipropyl-5-carboxamidotryptamine > 8-hydroxy-2(di-n-propylamino)-tetralin (8OH-DPAT) > buspirone > ipsapirone; the latter two compounds apparently behaved as partial agonists.
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4)
Other compounds displaying agonist activity in this system were: metergoline > methysergide ≥ rauwolscine ≥ cyanopindolol > yohimbine > (±)-4(3-tert-butyl-amino 2-hydroxypropoxy)-indol-2 carbonic acid isopropylester (21-009) > corynanthine.
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5)
Methiothepin, mianserin and spiperone displaced the concentration-effect curve of 5-HT to the right without depressing the E max value. The same held true for the partial agonists ipsapirone, buspirone and corynanthine.
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6)
The rank order of potency of agonists as well as of antagonists in this system was in full agreement with their affinities at 5-HT1D binding site. A highly significant correlation was found between both parameters (r = 0.94, P = 0.0001).
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7)
The results strongly support the contention that 5-HT1D binding sites are negatively coupled to adenylate cyclase in calf substantia nigra.
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Schoeffter, P., Waeber, C., Palacios, J.M. et al. The 5-hydroxytryptamine 5-HT1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra. Naunyn-Schmiedeberg's Arch Pharmacol 337, 602–608 (1988). https://doi.org/10.1007/BF00175784
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DOI: https://doi.org/10.1007/BF00175784