Homoepiboxidines: further potent agonists for nicotinic receptors.
Homoepiboxidine (3) and the corresponding N-methyl (4) and N-benzyl (5) derivatives were prepared from a 6beta-carbomethoxynortropane (8). Affinities and functional activities at neuromuscular, central neuronal and ganglionic-type nicotinic receptors were compared to those of epibatidine 1, and epiboxidine 2. Homoepiboxidine had equivalent affinity/activity to epiboxidine at neuromuscular, neuronal alpha4beta2, and most alpha3-containing ganglionic-type nicotinic receptors. The N-substituted derivatives showed reduced affinity/activity at most receptor subtypes. Replacement of the methylisoxazole moiety of 3 and 4 with a methyloxadiazole moiety provided analogues 6 and 7, which had greatly reduced affinity/activity in virtually all assays at nicotinic receptors. Marked analgetic activity in mice occurred at the following ip doses: epibatidine 10 microg/kg; epiboxidine 25 microg/kg; homoepiboxidine 100 microg/kg; N-methylhomoepiboxidine 100 microg/kg; the methyloxadiazole (6) 100 microg/kg. The time course at such ip doses was significantly longer for homoepiboxidine 3 with marked analgesia still manifest at 30 min post-injection. Epiboxidine and the homoepiboxidines were less toxic than epibatidine.
Fitch
Richard W
RW
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Pei
Xue-Feng
XF
Kaneko
Yumika
Y
Gupta
Tara
T
Shi
Dan
D
Federova
Irina
I
Daly
John W
JW
D000700:Analgesics / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000633:toxicity*; D008297:Male; D051379:Mice; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000633:toxicity*; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*
D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C106388:epiboxidine; C082748:epibatidine