"Phenyltropanes" redirects here. For an enumeration of their multiple types see list of phenyltropanes. Phenyltropanes were developed to reduce cocaine addiction and dependency. In general these compounds act. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues; this research has spanned beyond the last couple decades, has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction. The phenyltropane compounds were discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse and dependence liability. The first simple phenyltropanes to be made were shown to be active in behavioral assays only for the ββ-isomers; the activity of the corresponding αβ-isomers was disappointing. It was shown that WIN 35065-2 and WIN 34,428 are dopamine selective reuptake inhibitors with some residual actions at the norepinephrine transporter and serotonin transporter.
The neurotransmitter dopamine is a key candidate for explanation of reinforcing actions drugs. It's unclear. Animal studies show evidence. Animal studies on monkeys and rats have tried to assess the self-administration propensity of phenyltropane analogs alongside cocaine; the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding. Most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, cause nonselective reductions in cocaine intake relative to food. At the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy; this would mean that the agonists would need to be behaviorally active at the dose that can bring about reductions in cocaine craving. Most of the analogs will substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors. Since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability.
A slow onset, long-duration agonist seems like a reasonable approach. Phenyltropanes are used in animal studies of drug addiction as they share the stimulant properties and reinforcing effects of cocaine, but with higher potency, less non-specific binding which avoids the cardiotoxicity associated with cocaine. RTI-336 is an interesting example of a phenyltropane, being explored in the context of a treatment for cocaine addiction. RTI-336 is a DRI and thus targets the DAT, responsible for the addictive properties of cocaine. Although there may be a role for NET inhibition and acetylcholinergic actions it is DA, the critical neurotransmitter. Dopamine is a biological precursor to noradrenaline. DA is made from tyrosine, a non-essential amino acid given that it can be made from phenylalanine; the more attested habit creating methamphetamine is more serotonergic than the lesser reinforcing amphetamine. Most modern research suggests that 5-HT is negatively correlated with the addiction forming potential of psychostimulants, this is not saying that SRI properties cannot be considered beneficial.
In fact, the above was proven by Rothman for releasing agents under the PAL-287 program of related molecules. What was somewhat interesting is that although the reason for the lack of reinforcement of RTI-112 is now well established related RTI-111 was able to behave in ways that might be typical for a nonselective SNDRI such as cocaine; the role of the NET is not deleterious. In a recent paper by Rothman on transporter substrates, he establishes that for releasers that are amphetamine-like, discrimination stimulus is more dictated by NE release than DA release; this argument does not mitigate a case against the importance of DA, but is suggestive that catecholamine in general is important. The exact ratio being 50:50 in the case of methylphenidate. Desipramine and atomoxetine are not reliably self-administered though, whereas most selective DRIs are. SSRIs are not self-administered either. Hence, it should be borne in mind that these neurotransmitters are unlikely to be involved in the addiction forming properties of cocaine and related stimulants.
They are still behaviorally active and will contribute to the effects that such drugs elicit in their users. Promiscuity among transporters is worth bearing in mind. Monoamine transporters can transport neurotransmitters other than their "native" neurotransmitter; as an example, in the core of prefrontal cortex where DATs are low in number, DA is transported by the NET instead. Hence, selective NRIs such as atomoxetine are able to increase the concentration of supracellular DA in this brain region via NET blockade. Weeding out SERT and NET affinity is desirable in the context that these molecular targets are less relevant to the goals of the treatment program, to reduce cocaine intake, it can be seen that RTI-336 has fewer metabolically labile sites than cocaine, therefore has a longer duration span. These compounds are used in scientific research, as their high binding affinity for monoamine transporters, the wide range of radiolabelled phenyltropane compounds available with different binding specificities makes them useful for mapping the distribution of the various monoamine transporters in the brain.
Some phenyltropane derivatives have be
Kitty Kornered is a 1946 Looney Tunes cartoon, directed by Robert Clampett, produced by Edward Selzer and released by Warner Bros. Pictures. Considered among Clampett's best and wackiest films, Kitty Kornered was Clampett's final cartoon featuring longtime favorite Porky Pig, marks the only appearance of the Sylvester the cat in a Clampett-directed cartoon and only one of two times Sylvester spoke in a Porky Pig cartoon, it was the first appearance of Sylvester in the Looney Tunes series. This is the only cartoon where Sylvester has yellow eyes and a black nose; this is the first Looney Tunes cartoon to have the red and blue rings as well as the written out "That's all Folks!" at the closing rings. The Merrie Melodies music is heard at the end though. Porky and Sylvester would be paired in a trio of shorts directed by Chuck Jones: Scaredy Cat, Claws for Alarm, Jumpin' Jupiter. Both appeared in The Scarlet Pumpernickel as the villain roles; the neighborhood's cat owners all throw their cats out for the night.
Porky Pig attempts to do the same, but his four cats attempt to turn the tables and throw him out into the snow. Porky states. Porky bangs on the door, demanding to be let in, but the cats pop out of the door and proclaim in unison, "Milkman, keep those bottles quiet!", slam the door in his face which soon leads to a battle between Porky and his cats for the house. While the cats are lounging around, Porky bursts through the window, making an menacing face, he chases them around the house until one of them throws him into a cabinet full of dishes and a teapot. Porky retaliates by setting his pet dog "Lassie" on the cats; the cats see the dog's shadow and run for their lives, not knowing that "Lassie" is for real only a shadow puppet created with Porky's fingers and he doesn't for real have a dog. When Sylvester finds out that they've been tricked, he and the others plot revenge, exacted by having the cats create a War of the Worlds-esque sensation about invading aliens, disguising themselves as the aliens and driving Porky into a panic over "Men from Mars!".
Porky gets frightened and tries to shoot them with a gun but the cats, now dressed like Teddy Roosevelt, charge at Porky with swords and run him out of the house once and for all and winning the battle. Homeless and cold in the snow, Porky turns to the camera and asks the audience if they have a vacancy for a house. "Milkman, Keep Those Bottles Quiet" was a World War II hit song by Ella Mae Morse, was sung by Nancy Walker in the movie Broadway Rhythm. The wine that the grey drunken cat was drinking says "Arsenic and Old Grapes" is a parody to Arsenic and Old Lace. On Sylvester and Tweety Mysteries, the "Men from Mars" characters made an appearance in "Spaced Out"; the cats charging at Porky assume the appearances of Theodore Roosevelt and his Rough Riders cavalry. Quotations related to Kitty Kornered at Wikiquote Kitty Kornered on IMDb