Tropoxane is an aryloxytropane derivative drug developed by Organix Inc, which acts as a stimulant

Stimulant

Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...

 and potent dopamine

Dopamine

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 and serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 reuptake inhibitor

Reuptake inhibitor

A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...

. It is an analogue of dichloropane where the amine

Amine

Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

 nitrogen

Nitrogen

Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

 has been replaced by an oxygen

Oxygen

Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 ether

Ether

Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

 link (at the bridgehead

Bridgehead

A bridgehead is a High Middle Ages military term, which antedating the invention of cannons was in the original meaning expressly a referent term to the military fortification that protects the end of a bridge...

 position), demonstrating that the amine nitrogen is not required for DAT

Dopamine transporter

The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...

 binding and reuptake inhibition.

P. Meltzer et al. made some 8-thiabicyclo(3.2.1)octanes recently (2007).

For SAR purposes, a table has been included that lists some of these compounds.

MAT IC50 (nM) 8-thiabicyclo[3.2.1]octanes

X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
H	1a	910	>10uM	2a	140	>8uM	3a	117	>3uM
F	1b	220	>30uM	2b	59	>11uM	3b	38	494
Cl	1c	13	>10uM	2c	11	1uM	3c	9.6	33
Br	1d	9.1	>25uM	2d	6.0	342	3d	6.0	14
I	1e	6.7	>8uM	2e	9.0	70	3e	14	10
Cl2	1f	4.5	>3uM	2f	6.9	99	3f	5.7	8.0
BN	1g	8.0	>1uM	2g	8.0	36	3g	16	13

It had been hypothesized that transporter binding of the tropanes might include ionic bonding of the central tropane nitrogen. But it turned out that at this site neither ionic nor hydrogen bonding is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an N-replacement by methylene

Methylene

Methylene is a chemical species in which a carbon atom is bonded to two hydrogen atoms. Three different possibilities present themselves:* the -CH2- substituent group: e.g., dichloromethane ....

holds the potency within the same magnitude. However, N-quaternisation (N-dimethyl') considerably reduces DAT affinity.

2

In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2.

Both enantiomers, as well as the racemates are presented in several cases for comparison.

MAT IC50 (nM) Cl2 bicyclo[3.2.1]octanes

Enant.	X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
Rac	S	1a	4.5	3,600	2a	6.9	99	3a	5.7	8.0
Rac	O	1a	10	6,000	2a	3.1	64.5	3a	3.3	6.5
1R	NMe	1a	1.2	867	2a	0.4	27	3a	1.1	2.5
Rac	CH2	1a	7.1	5,160	2a	13	166	3a	9.6	33