Synthesis and pharmacological characterization of nicotinic acetylcholine receptor properties of (+)- and (-)-pyrido-[3,4-b]homotropanes.
(+/-)-Pyrido[3,4-b]homotropane [(+/-)-1] is a conformationally rigid analogue of nicotine (2) or nornicotine (3) that showed high affinity for nicotinic acetylcholine receptors. Even though the synthesis and potent activity of this highly interesting compound was originally reported in 1986 (Kanne, D. B.; Ashworth, D. J.; Cheng, M. T.; Mutter, L. C.; Abood, L. G. Synthesis of the first highly potent bridged nicotinoid. 9-Azabicylo[4.2.l]nona[2,3-c]pyridine (pyrido[3,4-b]homotropane). J. Am. Chem. Soc. 1986, 108, 7864-7865), the individual optical isomers have not been prepared and studied. In this study, we report the synthesis of (+)- and (-)-1 and show that (+)-1 has Ki = 1.29 nM at the alpha4beta2* nAChR and has over 260 times higher affinity than (-)-1. Single-crystal X-ray analysis of an intermediate used to prepare the isomers established the absolute stereochemistry as (1S,6S)-(+)-1 and (1R,6R)-(-)-1. Surprisingly, both isomers failed to produce antinociception in the mouse tail-flick and hot-plate assays, engender nicotine-like responding in rat drug discrimination, or alter current amplitude in alpha4beta2- and alpha3beta4-containing cells. However, (-)-1 antagonized nicotine-induced antinociception with an ED50 of 0.07 microg/kg in the tail-flick assay. The reason for this unusual pharmacology is unknown, but it is possible that (-)-1 is acting at a non-epibatidine-sensitive receptor subtype to antagonize nicotine's effects in the tail-flick assay.
Carroll
F Ivy
FI
Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Hu
Xingding
X
Navarro
Hernán A
HA
Deschamps
Jeffrey
J
Abdrakhmanova
Galya R
GR
Damaj
M Imad
MI
Martin
Billy R
BR
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000700:Analgesics; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014326:Tropanes; C055134:pyrido(3,4-b)norhomotropane; D009538:Nicotine