Selective reversible and irreversible ligands for the kappa opioid receptor.
(+-)-(5 beta,7 alpha,8 beta)-3,4-Dichloro-N-methyl-N-[3-methylene-2- oxo-8-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5 alpha,7 alpha,8 beta) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps. Compound 14, which we have designated SMBU-1, was found to bind with moderate affinity (Ki = 109 nM) and good selectivity (mu/kappa = 29) to the kappa opioid receptor, while 15 was only 1/10 as potent as a kappa ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of kappa-receptor binding (69 +/- 6% of control at 10(-6) M). The ketone precursor trans-N-methyl-N-[5-oxo-2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher kappa-affinity (Ki = 78 nM) and a much higher kappa-selectivity (mu/kappa = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased kappa-selectivity (mu/kappa = 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the kappa-selective analgesic spiradoline (U-62,066), demonstrated the highest kappa-affinity (Ki = 1.5 nM) and kappa-selectivity (mu/kappa = 468) observed in this series.
Cheng
C Y
CY
School of Pharmacy, College of Medicine, National Taiwan University, Taipei.
Wu
S C
SC
Hsin
L W
LW
Tam
S W
SW
D044482:Benzeneacetamides; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D044482:Benzeneacetamides; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C075255:3,4-dichloro-N-methyl-N-(3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-7-yl)benzeneacetamide; C051272:spiradoline