Several neoclerodanes, such as salvinorin A (1) and herkinorin (3), have recently been shown to possess opioid receptor activity in vitro and in vivo. To explore the structure-affinity relationships of this interesting class of compounds, we have synthesized a series of analogues from 1 isolated from SalVia diVinorum. Here, we report the semisynthesis of neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further development of novel opioid receptor ligands.SalVia diVinorum is a plant from the mint family that has been used in the traditional spiritual practices by the Mazatec Indians of Oaxaca, Mexico. Chewing fresh leaves or smoking dried leaves will produce hallucinogenic-like experiences. 1 These experiences last for up to an hour and are reported to be potent and intense. [2][3][4][5] These effects, however, appear to be different than other hallucinogenic substances such as LSD or DOB. Recreational use of S. diVinourm is increasing in part due to its availability for purchase through the Internet. 6 The main active constituent isolated from the leaves of S. diVinorum is salvinorin A (1), a neoclerodane diterpene. 7,8 Compound 1 was found to be a potent and selective κ opioid receptor (κOR) agonist. 9-11 Interestingly, the pharmacology of 1 appears to be different than other κ agonists. 12 Recent work has shown that 1 decreases dopamine levels in the caudate putamen of mice and that this effect is blocked by the κOR antagonist nor-binaltorphimine. 13 A study has also shown that 1 dose dependently increases immobility in the forced swim test, indicating that 1 has depressivelike effects. 14 Furthermore, 1 disrupts climbing behavior on an inverted screen task. 15 This study showed that there are differences in the susceptibility of 1 and the standard κOR agonist U69,593 to antagonism by nor-binaltorphimine. This finding also indicates that 1 may bind in a manner that is qualitatively different than traditional κOR ligands.Recently, we described the synthesis of several analogues of 1 that were found to be opioid receptor ligands. 11 Among these compounds described were analogues 2-4. Propionate 2 was found to have approximately the same affinity for the κOR as 1 but was less potent as an agonist. This work also identified herkinorin (3), the first neoclerodane diterpene with µ opioid receptor affinity, and WH-1-32 (4), an analogue slightly more potent than 1 as a κOR agonist. 11 Recently, methoxymethyl analogue 5 16 and carbamate 6 17 were identified as having affinity for κORs similar to 1. Interestingly, 5 was found to be a full agonist more potent than 1, and 6 is a partial agonist at κORs. These observations illustrate that substitution at the C-2 position can have profound effects on opioid receptor affinity and activity.Recently, a model was proposed for the binding of 1 to the κOR. 18 This model was developed through the use of molecular modeling and mutagenesis studies. However, the binding pocket of salvinorin A will not be known until the ...

The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the sigma receptors (e.g.28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.