User:Nuklear/Peridine

Pethidine is a weak μ-opioid with serotonergic activity, 68 years old. It's abuse potential is limited by its acute toxicity.

SAR #1
(S.A. Lomenzo, et al.) Cocaine binding to DAT is well established. Initially, specific binding sites were identified in rodent brain that bind [3H] cocaine at a single saturable site (Reith, et al. 1980) Subsequent studies using rodent, human, and nonhuman primate (Madras, et al) brain tissue preparations later provided evidence that suggests DAT cocaine binding is heterogenous. Two distinct binding sites on the DAT have been proposed: ↑ and ↓ affinity binding sites. These sites are termed high and low affinity based upon the relative affinity of cocaine for these sites. The PT analogs of cocaine, specifically WIN 35,428, WIN 35,065-2, and WIN 35,981, in addition to several other cocaine-like compounds have binding curves that better fit a two-site than a one-site model. However, it is uncertain if these compounds interact at the ↑ and ↓ affinity sites in a fashion similar to cocaine. It may be possible for compounds other than cocaine to have a ↑-affinity for the ↑-affinity site and vice versa. Alternatively, DAT inhibitors such as mazindol,<> and Vanoxerine exhibit only single site affinity at the DAT.

A strong correlation between DAT binding affinity and potency for reinforcing effects among coke/analogs has been reported (Ritz, et al. 1987). For other effex of coke/analogs, correlation between DAT affinity and potency can depend on whether high-affinity or low-affinity sites are examined. E.g., in comparison of DAT binding affinity with the cocaine-like discrimulative-stimulus effects, the correlation between substitution potencies for cocaine analogs and DAT binding is greater for the ↑-affinity constants than for the corresponding ↓-affinity constants (J. Katz, et al. 2000).

Currently there are no known DARIs that discriminate between ↑ and ↓ affinity DAT sites. However, it has been reported that meperidine is a potent inhibitor of [3H]DA reuptake when examined in a chopped tissue rather than synaptosomal preparation. Further, the conc. response curve exhibited a plateau at ~20% inhibition over a broad range of low concs of meperidine. This ↑-affinity DARI component produced by meperidine at ↓-concs was also consitent with the amount of total binding of [3H]WIN 35,428 that is attributable to ↑-affinity sites. In addition, when the opioid-agonist actions of meperidine were blocked by naltrexone, meperidine substituted for cocaine in squirrel monkeys.

SAR #2
(Rhoden et, al.) Merperidine was initially found to be selective for the SERT over the DAT. Further exploration of various aryl-substituted piperidine analogs revealed that although DAT affinity of these compounds could be enhanced, high SERT affinity and selectivity predominated throughout the series. "Effects of the aryl substituent on DAT affinity of meperidine analogs paralleled the SAR previously reported for PT's, etc." From the SAR of the meperidine analogs, the m,p-Cl2 analog was identified as an important moiety for molecular recognition at the DAT. However, even though this analog had the greatest DAT affinity in the whole series, it was still marginally SERT selective, suggesting that the 4,4-disubstituted piperidine meperidine scaffold is intrinsically SERT selective. The inherent SERT selectivity of the meperidine analogs warrented an investigation of the SAR at MATs to elucidate further the pharmacophore requirements at both DAT & SERT. All the further analogs in the present study have been based around the m,p-Cl2 phenyl substitution pattern.

Results
In an attempt to specifically increase potency and selectivity for either the DAT or the SERT, various substitutions on the ester group and on the nitrogen atom as well as modifications of the ester molecule were 'considered'.

In conclusion, the results of this study clearly demonstrate that meperidine and its analogs are selective ligands for the SERT over the DAT. Chemical modification of the ester group generally led to compounds with increased SERT affinity. Interesting that the m-monochloro substitution pattern and ketobemidone propionyl FG were not examined. Replacing nitrogen with sulfur is also a possible.