Anita H. Lewin

Designer drugs: a medicinal chemistry perspective

There are numerous medicinal chemistry reports in the literature describing the pharmacological properties of thousands of narcotics, stimulants, hallucinogens, sedative‐hypnotic drugs, cannabinoids, and other psychoactive substances as well as synthetic methods for their preparations. This information, while essential for the advancement of science, has been used by clandestine chemists to manufacture and market an endless variety of analogs of so‐called designer drugs. In this review, we describe how clandestine chemists used the principles of medicinal chemistry to design molecules, referred to as designer drugs, that elicit the effects of opioids, amphetamine and analogs, cannabinoids, and phencyclidine analogs while circumventing the law.

Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates

1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks (ED50 234 mg/kg) the convulsions and deaths produced by N-methyl-D-aspartate (125 mg/kg) in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole (80 mg/kg), strychnine (2 mg/kg), bicuculline (6 mg/kg), or maximal electroshock (50 mA, 0.2 s), and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent (IC50 greater than 40 microM) than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive [3H] glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action. These findings suggest that 1-aminocyclopropanecarboxylates may be useful in the treatment of neuropathologies associated with excessive activation of N-methyl-D-aspartate receptor coupled cation channels.

New, potent cocaine analogs: ligand binding and transport studies in rat striatum

Two potent cocaine analogs have been developed that have the highest known affinities for the cocaine binding site in rat striatum. Both 3 beta-(4-chlorophenyl)- (RTI-COC-31) and 3 beta-(4-methylphenyl)-tropane-2-carboxylic acid methyl ester (RTI-COC-32) compete for [3H]WIN 35,428 and [3H]mazindol binding with a IC50 that is 100 times more potent than that of (-) cocaine. Additionally, these compounds inhibit [3H]dopamine uptake with a similar, high potency. These results may lead to the development of high affinity probes for the cocaine binding site.

Receptors of mammalian trace amines

The discovery of a family of G-protein coupled receptors, some of which bind and are activated by biogenic trace amines, has prompted speculation as to the physiological role of these receptors. Observations associated with the distribution of these trace amine associated receptors (TAARs) suggest that they may be involved in depression, attention-deficit hyperactivity disorder, eating disorders, migraine headaches, and Parkinsons disease. Preliminary in vitro data, obtained using cloned receptors, also suggest a role for TAARs in the function of hallucinogens.

Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: Possible confounding effects on in vivo and in vitro studies

SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure.

High specific activity tritium-labeled N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (INBMeO): a high-affinity 5-HT2A receptor-selective agonist radioligand.

The title compound ([3H]INBMeO) was prepared by an O,O-dimethylation reaction of a t-BOC protected diphenolic precursor using no carrier added tritiated iodomethane in DMF with K(2)CO(3). Removal of the t-BOC protecting group and purification by HPLC afforded an overall yield of 43%, with a radiochemical purity of 99% and specific activity of 164Ci/mmol. The new radioligand was suitable for labeling human 5-HT(2A) receptors in two heterologous cell lines and had about 20-fold higher affinity than [(3)H]ketanserin.

Selective dopamine transporter inhibition by cocaine analogs.

Several isopropyl and phenyl esters of 3 beta-(4-substituted phenyl) tropan-2 beta-carboxylic acid analogs of cocaine are relatively more potent and selective than cocaine and some other compounds in inhibiting dopamine uptake. These analogs can be used as binding ligands and as tools for elucidating the mechanisms of action of cocaine.

High potency cocaine analogs: Neurochemical, imaging, and behavioral studies

Recent evidence suggests the behavioral properties of cocaine are related to its ability to inhibit dopamine (DA) reuptake.1.2 Specific binding sites tbr cocaine have been identified with a host of Iqpnds, including [3H]cocaine.3-5 However, the use of [3H]cocaine as a ligand presents many problems, including its low affinity and rapid dissociation rate. While other non-cocaine-like lignds such as GBR 12935, mazindol, and nomifensine overcome the problems of low affinity and rapid dissociation, they present problems of their own. These ligands bind to a single high aflinity site, while cocaine binds to both a high and low affinity site. Furthermore, Madras et af .6 reported that [3H]cocaine was not l l l y displaced by these non-cocaine-like drugs. Thus it appears that in order to correctly identify the molecular structural requirements fbr cocaine binding one must utilize cocaine or cocaine analogs. It was reported by Clarke et af.7 that removal of the ester linkage between the phenyl ring and tropane ring of cocaine (FIG. 1) results in the compound designated WIN 35,065-2. This compound demonstrated a hlgher affinity for the dopamine transporter than cocaine itself. Addition of fluorine to the pm-position of the phenyl ring (WIN 35,428, also designated CET) hrther enhanced potency. Both WIN 35,065-2 and WIN 35,428 have been radioactively labeled and have proven to be superior ligands fbr in vim binding studies when compared to cocaine.6*8

Positive identification and quantitation of isomeric cocaines by high-performance liquid chromatography

A high-performance liquid chromatographic procedure for separating and identifying the four isomeric cocaines has been developed. Use of this procedure with an internal standard allows for the determination of the quantity of any isomeric cocaine in an unknown sample. The pitfalls and problems encountered in the use of gas chromatography and mass spectrometry in the analysis of cocaines and ecgonine methyl esters are discussed.

Structure-Activity Correlations for β-Phenethylamines at Human Trace Amine Receptor 1

A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of beta-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat G alpha(s). Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r(2) of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.