Analogues of (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Synthesis and in vitro and in vivo opioid receptor antagonist activity.
The synthesis of compounds 6, 7a,b, 8a,b, 9a,b, and 10a,b where the amino -NH- group of JDTic (3) was replaced with an aromatic horizontal lineCH-, CH(2), O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of kappa opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar K(e) values at the kappa opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH(2)-) group. This compound had a K(e) = 0.18 nM and was 37- and 248-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective kappa agonist U50,488-induced diuresis after sc administration in rats. In contrast to 3, where kappa antagonist activity lasted for three weeks, compound 7a did not show any kappa antagonist activity after one week.
Runyon
Scott P
SP
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Brieaddy
Lawrence E
LE
Mascarella
S Wayne
SW
Thomas
James B
JB
Navarro
Hernán A
HA
Howard
James L
JL
Pollard
Gerald T
GT
Carroll
F Ivy
FI
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004231:Diuresis / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
C551622:6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid-(1-(4-(3-hydroxyphenyl)dimethylpiperidinylmethyl)methylpropyl)amide; D007546:Isoquinolines; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013764:Tetrahydronaphthalenes; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer