XAMI and DCDM, agonists at cAMP-associated octopamine receptors in cockroach nerve cord, produce centrally mediated antinociception in mice.
The ability of XAMI (2,3-xylylaminomethyl-2'-imidazoline), the most potent agonist of cAMP-associated octopamine-sensitive adenylate cyclase in cockroach (Periplaneta americana) nerve cord yet reported, and DCDM (N-demethylchlordimeform), a partial octopamine agonist in this preparation, to produce centrally mediated antinociception in mice was evaluated. The antinociception produced by these compounds was compared to that previously reported for p-octopamine, a phenylethylamine and endogenous mammalian hydroxyphenolic analog of norepinephrine. Consonant with the reported greater agonistic activity of XAMI on octopamine-sensitive adenylate cyclase, XAMI was more potent than p-octopamine by spinal or supraspinal administration in the abdominal constriction test (E50 = 0.013 micrograms i.t., 1.45 micrograms i.c.v.) and in the 48 degrees C hot-plate test (ED50 = 0.06 micrograms i.t., 0.4 micrograms i.c.v.), but was inactive in the tail-flick test (up to 4.0 micrograms i.c.v. or i.t.). Unlike p-octopamine, both XAMI and DCDM were active by peripheral routes of administration. DCDM was orally active in the mouse acetylcholine-induced abdominal constriction test (ED50 = 9.98 mg/kg p.o.) and was active via the s.c. route in this test (ED50 = 2.36 mg/kg), the 48 degrees C hot-plate test (ED50 = 5.40 mg/kg) and the tail-flick test (ED50 between 15 and 30 mg/kg). It appeared to be a full agonist against these endpoints. XAMI produced dose-related antinociception in the abdominal constriction test (ED50 = 0.10 mg/kg s.c.) and in the 48 degrees C hot-plate test (ED50 = 3.71 mg/kg p.o. and 0.46 mg/kg s.c.), where the antinociceptive response persisted for at least 60 min following subcutaneous or oral administration. Both compounds were less potent via peripheral routes than clonidine (as reference) in these tests. Mechanistically, XAMI-induced antinociception was antagonized by yohimbine and idazoxan, but not the opiate antagonist naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)
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Drug Discovery Research, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
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Connelly
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Hollingworth
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D000067956:Adenylyl Cyclase Inhibitors; D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002742:Chlorphenamidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D004146:Dioxanes / Q000494:pharmacology; D004347:Drug Interactions; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009655:Octopamine / Q000494:pharmacology; D010526:Periplaneta / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D017982:Receptors, Biogenic Amine; D015016:Yohimbine / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D004146:Dioxanes; D007093:Imidazoles; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D017982:Receptors, Biogenic Amine; C027604:norsynephrine receptor; D009655:Octopamine; D010656:Phenylephrine; C011741:demethylchlordimeform; D015016:Yohimbine; D009270:Naloxone; C073298:2,3-xylylaminomethyl-2'-imidazoline; D000242:Cyclic AMP; D002742:Chlorphenamidine; D019329:Idazoxan