Synthesis and neuropharmacological evaluation of R(−)-N-alkyl-11-hydroxynoraporphines and their esters

New Dopamine D2 Receptor Agonist, [3H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo

“…(B,C) HPLC chromatograms of (B) [ 3 H]­MCL-536 and (C) coinjected nonradioactive MCL-536. Reagents and conditions: (a) ref ; (b) IBX, anhydrous DMF, rt, 76%; (c) 3-fluoropropanol, methanesulfonic acid, 95–105 °C, 44%; 1 N HCl/Et 2 O, 100%; ,− (e) [ 3 H] 2 , [Pd], 60 Ci/mmol.…”

“…The N -allyl precursor to [ 3 H]­MCL-536, MCL-565, was synthesized in seven steps from commercially available morphine (Figure ), and tritiated to produce [ 3 H]­MCL-536 at >99% purity and activity of 57.6 Ci/mmol. ,− …”

Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

“…For the synthesis of morphine analogues (Scheme 2), morphine was treated with 1 equivalent of PhNTf 2 and Et 3 N in dichloromethane to selectively afford morphine-3-triflate 7 . 21 The 6-hydroxy group was protected by TBDPSCl/Et 3 N to afford 8 . 14 The triflate was converted to 3-aminomorphine ( 9 ) by using Pd catalyzed amination with benzophenoneimine, followed by hydrolysis under acidic conditions.…”

Oral r-(-)-11-o-valeryl-n-n-propylnoraporphine reverses motor deficits in mptp-treated marmosets

“…Apomorphine is the only dopamine agonist drug thought to have clinical efficacy equivalent to that of l ‐dopa . This may be explained by its relatively nonselective activity at D1 (Ki, 48‐1010 nM), D2 (Ki, 2‐18 nM), and D3 (Ki, 26‐130 nM) receptors compared to the more limited D2/D3 receptors actions of other dopamine agonists, such as ropinirole and pramipexole . Apomorphine has to be administered subcutaneously because its oral bioavailability is very poor as a result of extensive first‐pass metabolism .…”

“…However, this molecule was not pursued because tolerance developed and efficacy was lost after a short treatment period . Another novel derivative, R‐(‐)‐11‐O‐valeryl‐N‐ n ‐propylnoraporphine (11‐OH‐NPa valerate), which has a similar D1 and D2 binding profile to apomorphine (D1 Ki, 699 nM; D2 Ki, 29 nM), was shown to have potent dopaminergic agonist activity in rodent studies . In addition, in rodents, oral administration of 11‐OH‐NPa valerate induced stereotyped behavior that was reversed by haloperidol, enhanced apomorphine‐induced locomotor activity, and induced rotation in 6‐OHDA‐lesioned rats, suggesting effective dopamine agonist activity .…”