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STEREOISOMERISM AND MUSCARINIC RECEPTOR AGONISTS - SYNTHESIS AND EFFECTS OF THE STEREOISOMERS OF 3-[5-(3-AMINO-1,2,4-OXADIAZOL)YL]-1-AZABICYCLO[2.2.1]HEPTANE

POMBOVILLAR, E., WIEDERHOLD, KH., MENGOD, G., PALACIOS, JM., SUPAVILAI, P. & BODDEKE, HWGM., 3-Aug-1992, In : European journal of pharmacology-Molecular pharmacology section. 226, 4, p. 317-325 9 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • E POMBOVILLAR
  • KH WIEDERHOLD
  • G MENGOD
  • JM PALACIOS
  • P SUPAVILAI
  • HWGM BODDEKE

The preparation and the biological activities of the four stereoisomers of 3-[5-(3-amino-1,2,4-oxadiazol)yl]-1-azabicyclo [2.2.1]heptane are described. The most potent stereoisomer, 3a, has the 3R,4R configuration, and in vitro activities in (pD2(% efficacy): ileum 8.8 (87%), hippocampus 9.8 (116%) and ganglion 10.2 (36%)). 3b (3S,4S) was weaker (ileum 8.1 (121%), hippocampus 8.5 (107%), ganglion 9.0 (63%)). The other two stereoisomers, 4a (3S,4R; ileum 7.1 (108%), hippocampus 8.2 (116%), ganglion 7.3 (31%)) and 4b (3R,4S; ileum 7.0 (100%), hippocampus 7.0 (120%), ganglion 7.2 (67%)) are of comparable activity, with an analogous profile to that of the more potent stereoisomers. Thus, compounds 3a and 4a, possessing the 4R stereochemistry, showed selectivity for the hippocampus over the ileum. Compound 3a was, however, more potent in the ganglion than in the hippocampus. All four stereoisomers were full agonists in the hippocampus, indicating M1 activity; however, they were partial agonists in the depolarisation of the rat superior cervical ganglion, another M1-mediated response. This may be due to M2-mediated hyperpolarization. With 3a (0.01 mg/kg i.p.), expression of c-fos mRNA was observed in the hypothalamus and in brain areas involved in sensory processing; these effects were totally blocked by pretreatment with 2 mg/kg scopolamine. In particular, activation of the superior colliculus is consistent with potent M2 activity.

Original languageEnglish
Pages (from-to)317-325
Number of pages9
JournalEuropean journal of pharmacology-Molecular pharmacology section
Volume226
Issue number4
Publication statusPublished - 3-Aug-1992

    Keywords

  • MUSCARINIC RECEPTOR SUBTYPES, MUSCARINIC RECEPTOR AGONISTS, STEREOCHEMISTRY (ABSOLUTE), SUPERIOR CERVICAL GANGLION (RAT), HIPPOCAMPAL SLICE (RAT), ILEUM (GUINEA PIG), C-FOS EXPRESSION, HYBRIDIZATION (INSITU), SUPERIOR CERVICAL-GANGLION, RAT CEREBRAL-CORTEX, CHOLINERGIC AGONISTS, MESSENGER-RNA, RECOGNITION, PILOCARPINE, BRAIN, GENE, FOS

ID: 14148851