Potent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3R)-7-Hydroxy-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (PDTic)

Abstract

Past studies have shown that it has been difficult to discover and develop potent and selective κ opioid receptor antagonists, particularly compounds having potential for clinical development. In this study, we present a structure-activity relationship (SAR) study of a recently discovered new class of tetrahydroisoquinoline κ opioid receptor antagonists which led to (3 R)-7-hydroxy- N-{(1 S)-2-methyl-1-[(-4-methylpiperidine-1-yl)methyl]propyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (12) (4-Me-PDTic). Compound 12 had a K = 0.37 nM in a [S]GTPγS binding assay and was 645- and >8100-fold selective for the κ relative to the μ and δ opioid receptors, respectively. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low molecular weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that 12 does indeed penetrate the brain.

Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist

“…The Schild analysis showed that 34 has a linear plot with a slope of −0.92, indicating that 34 is likely a competitive antagonist (Figure B,C). An apparent K e value was also calculated using the equation described previously: K e = [ L ]/(( A ′/ A ) – 1), where [ L ] is the test compound concentration, A ′ is the EC 50 value of PEA with 34 , and A is the EC 50 value of PEA alone. ,,− In our assay, 34 has an apparent K e value of 4.0 ± 0.6 nM, which is consistent with the estimated pA2 value determined from the Schild plot (5 nM, x -intercept).…”

Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1

“…Apparent K e values were calculated using the equation K e = [L]/((A′/A) -1), where [L] is the concentration of test compound, A′ is the EC 50 value of PEA in the presence of antagonist, and A is the EC 50 value of PEA in the absence of antagonist. 35,37,[39][40][41][42][43] K e values were considered valid when the ER was at least 4. In the curve shift assay, antagonist 1 has a K e value of 110 nM, while antagonist 2 has a K e value of 159 nM.…”

Potent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3R)-N-[1R)-1-(Cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (CDTic)

“…It is well documented that methyl groups can have a significant effect on the potency of target compounds. , Furthermore, in a recent study, we found that the addition of a methyl group to the 4-position on the piperidine ring of compound 42 to give the 4-methyl analogue 4-MePDTic ( 43 ) resulted in a 18-fold increase in the κ opioid receptor potency relative to 42 ; therefore, we investigated the effect of adding a 4-methyl group to 1 (Table ). Compound 18 , which is the 4-methyl analogue of 1 , has a K e = 1.27 nM at the κ opioid receptor and thus is 9 times less potent than 1 , which has a K e = 0.14 nM at the κ opioid receptor.…”

“… a Data are mean ± SEM of at least three independent experiments conducted in duplicate. None of the compounds had agonist activity at 10 μ M. b Taken from ref 22. c 88:12 mixture of isomers by HPLC. d Taken from ref 24. …”