Faculty Bibliography

The conformation and alignment of cocaine analogues bound to the monoamine transporter proteins were explored using the tensor decomposition 3-D QSAR method. It is proposed from these calculations that the bound conformation of these ligands to the three transporter proteins has the 3beta-aryl substituent in a conformation in which the aryl group is orthogonal or approximately orthogonal to the tropane ring. Based on these results, rigid and semi-rigid tropane analogues were designed, synthesized and their affinities for the monoamine transporters were determined

A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-methylene butyl linker produced very potent compounds for both the D2 and D3 receptors. Further structure-activity studies led to a novel template showing 50- to 100-fold selectivity for the D3 receptor

A series of substituted N-benzyl analogues of the dopamine transporter (DAT) specific compound, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine were synthesized and biologically characterized. Different 4'-alkyl, 4'-alkenyl, and 4'-alkynyl substituents were introduced in the phenyl ring of the benzyl moiety along with the replacement of the same phenyl ring by the isomeric alpha- and beta-naphthyl groups. Different polar substitutions at the 3'- and 4'-position were also introduced. Novel compounds were tested for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in the brain by competing for [(3)H]WIN 35 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [(3)H]dopamine. Binding results demonstrated that alkenyl and alkynyl substitutions at the 4'-position produced potent compounds in which compound 6 with a vinyl substitution was the most potent. In vivo evaluation of three selected compounds indicated that despite their high potency at the DAT, these compounds stimulated locomotor activity (LMA) less than cocaine when tested across similar dose ranges. In a drug discrimination study procedure, none of these three compounds generalized from cocaine in mice trained to discriminate 10 mg/kg cocaine from vehicle. In a 4 h time course LMA experiment, one of our previous lead piperidine derivatives (1a) showed considerable prolonged action. Thus, in this report, we describe a structure-activity relationship study of novel piperidine analogues assessed by both in vitro transporter assays and in vivo behavioral activity measurements

Investigated the preferential increase of extracellular dopamine (DA) in the nucleus accumbens (NA) relative to the caudate-putamen after systemic cocaine administration in male rats. Cocaine was compared with 2 other blockers of

Examined whether dopamine (DA) release in the nucleus accumbens (NACC) following 5-hydroxytryptamine (5-HT) type 2A receptor stimulation is potentiated by intermittent cocaine administration in male rats. Ss received daily injections of either cocaine or saline for 14 days. On the 7th day of withdrawal, Ss were administered the 5-HT receptor agonist (+or-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) with or without the 5-HT receptor antagonist ketanserin. Results showed that activation of 5-HT-sub(2A ) receptors within the NACC produced greater and longer-lasting increases in extracellular DA in Ss pretreated with cocaine than in those pretreated with saline. The DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin. It is concluded that intermittent cocaine may cause enhanced sensitivity of 5-HT-sub(2A ) receptors within the NACC.