Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents:  Restricted Rotation Analogues of Methylphenidate

Abstract

A series of threo-1-aza-3 or 4-substituted-5-phenyl[4.4.0]decanes (quinolizidines), which were envisioned as restricted rotational analogues (RRAs) of methylphenidate (MP), was synthesized and tested for inhibitory potency against [(3)H]WIN35,428, [3H]citalopram, and [3H]nisoxetine binding to the dopamine, serotonin, and norepinephrine transporters, respectively. Two different synthetic schemes were used; a Wittig reaction or acylation (followed by an intramolecular condensation) was a key feature of each scheme. The unsubstituted RRA, threo(trans)-1-aza-5-phenyl[4.4.0]decane (12a), was equipotent to unconstrained threo-MP against [(3)H]WIN35,428 binding. The extra ring in these RRAs (which reduces the conformational freedom) and the orientation and polarity of substituents at the 4-position on this extra ring are of critical importance to the biological activity. Generally, the RRAs paralleled the corresponding unconstrained MP derivatives in binding affinity to the three transporters. The results suggest that the conformation of MP in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N-H may be the bioactive form of the molecule.

Analysis of six ‘neuro‐enhancing’ phenidate analogs

“…However, unlike cocaine, nearly no activity at the serotonin transporter (SERT) has been reported. [6][7][8] Methylphenidate increases central nervous system activity, and effects at lower doses include improved cognition, heightened alertness, and reduced fatigue whereas higher doses can induce euphoria. [9][10][11][12] On these grounds methylphenidate has been abused as a recreational drug since the 1960s and more recently as a 'neuro-enhancing', 'smart drug'.…”

The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters

“…The 3β-(3,4-dichlorophenyl)-substitution was selected because this 3,4-dichloro motif has offered among the most potent DAT and SERT inhibitors available. 13,38,39 The linking-chain lengths were restricted to a maximum of 10 intervening methylene groups. Consequently interaction of each of the tropane moieties of the bivalent ligands with tropane binding sites on adjacent DATs of a DAT dimer would be highly unlikely.…”

Continuous-Flow Hydrogenation of 4-Phenylpyridine to 4-Phenylpiperidine with Integrated Product Isolation Using a CO2 Switchable System

“…Under harsh conditions (>250°C and >130 atm), Re 2 S 7 can selectively hydrogenate aryl-substituted pyridines to arylpiperidines [11,12]. Heterogeneous Pt/C [13] and PtO 2 [14][15][16][17] were also used to hydrogenate arylpyridines at room temperature, and in all cases, the addition of acids was needed to avoid poisoning [18] of Pt catalysts. In general, Pt catalysts have shown little selectivity and fully hydrogenated cyclohexylpiperidines compounds were obtained, except for the case of sterically encumbered 2-phenylpyridines where 2-phenylpiperidine could be obtained in moderate to good yields of 60-90% [13][14][15][16][17].…”

“…Heterogeneous Pt/C [13] and PtO 2 [14][15][16][17] were also used to hydrogenate arylpyridines at room temperature, and in all cases, the addition of acids was needed to avoid poisoning [18] of Pt catalysts. In general, Pt catalysts have shown little selectivity and fully hydrogenated cyclohexylpiperidines compounds were obtained, except for the case of sterically encumbered 2-phenylpyridines where 2-phenylpiperidine could be obtained in moderate to good yields of 60-90% [13][14][15][16][17]. Recently, Kappe et al reported a detailed study on continuous-flow hydrogenation of pyridines using Pt/C or Rh/C and glacial acetic acid as solvent including one example of an aryl-substituted pyridine [19,20].…”