| High binding affinity for mu and kappa opioid receptors has been observed for analogues of cyclazocine [(+/-)-2], ethylketocyclazocine [EKC, (+/-)-1], naltrexone [(+/-)-16], and morphine [(+/-)-11] where the phenolic OH group was replaced with a formamide (-NHCHO) group. For the cyclazocine core, Ki (nM) values of 8-formamidocyclazocine [8-FAC, (+/-)- 43] are 1.9 and 0.85 for mu and kappa opioid receptors, respectively. The binding of the 3-formamido analogue of cyclazocine is highly enantiospecific (eudismic ratios ∼ 2000 for mu and kappa) with K i values ≤1 nM observed for the (2R, 6R, 11R)-isomer (+/-)-46. For the EKC core, the 8-formamido analogue (+/-)-50 displayed high opioid receptor binding affinity [Ki (nM) for mu and kappa opioid receptors = 6.1 and 1.2, respectively]. For the naltrexone core, the 3-formamido analogue (+/-)-78 displayed nanomolar opioid receptor binding affinity [Ki (nM) for mu and kappa opioid receptors = 8.3 and 4.2, respectively]. High binding affinity for mu and kappa opioid receptors has also been observed in other analogues of cyclazocine including the 8-thioformamido analogue (+/-)- 91 [Ki (nM) for mu and kappa opioid receptors = 0.76 and 0.63, respectively] and the isoquinolone derivative (+/-)- 111 [Ki (nM) for mu and kappa opioid receptors = 5.5 and 0.74, respectively]. All 8- or 3-formamido analogues were synthesized from the corresponding 8- or 3-amino analogues, which were prepared from the corresponding triflates using palladium-catalyzed amination methodology. The isoquinolone derivative (+/-)-111 was synthesized from the 8-CONHOCH3 analogue (+/-)-32 using a lithiation procedure. Key steps in the total synthesis of the EKC analogue (+/-)- 50 include an effective lithiation procedure leading to the key intermediate 3-methyl-4-ethyl-pyridine (46) and the preparation of 4-methoxybenzylmagnesium chloride (63) using mechanically activated magnesium. |
