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21-414: Alazocine shows stereoselectivity in its pharmacodynamics . The (−)-enantiomer is a non-selective and high- affinity ligand of the μ- , κ- , and δ-opioid receptors (K i = 3.0, 4.7, and 15 nM in guinea pig brain membranes ) with very low affinity for the sigma σ 1 receptor (K i = 1,800–4,657 nM in guinea pig brain membranes). It acts as a moderate- efficacy partial agonist of

42-430: A chiral catalyst, an enzyme or a chiral reagent. The degree of selectivity is measured by the enantiomeric excess . An important variant is kinetic resolution , in which a pre-existing chiral center undergoes reaction with a chiral catalyst, an enzyme or a chiral reagent such that one enantiomer reacts faster than the other and leaves behind the less reactive enantiomer, or in which a pre-existing chiral center influences

63-520: A racemate into a pure enantiomer or into a mixture in which one enantiomer is present in excess, or of a diastereoisomeric mixture into a single diastereoisomer or into a mixture in which one diastereoisomer predominates). An example of modest stereoselectivity is the dehydrohalogenation of 2-iodobutane which yields 60% trans -2-butene and 20% cis -2-butene. Since alkene geometric isomers are also classified as diastereomers, this reaction would also be called diastereoselective. Cram's rule predicts

84-463: Is a selective partial agonist of the κ-opioid receptor, antagonist of the μ-opioid receptor, and to a far lesser extent agonist of the δ-opioid receptor with very low affinity for the sigma receptors, while (+)-alazocine is a selective agonist of the sigma σ 1 receptor and to a lesser (~10-fold) extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ 2 receptors. Alazocine

105-404: Is an example of an enantioselective process, in which an achiral allylic alcohol substrate is transformed into an optically active epoxyalcohol. In the case of chiral allylic alcohols, kinetic resolution results. Another example is Sharpless asymmetric dihydroxylation . In the example below the achiral alkene yields only one of the possible 4 stereoisomers. With a stereogenic center next to

126-513: Is concerned solely with the products, and their stereochemistry. Of a number of possible stereoisomeric products, the reaction selects one or two to be formed. Stereomutation is a general term for the conversion of one stereoisomer into another. For example, racemization (as in S N 1 reactions), epimerization (as in interconversion of D-glucose and D-mannose in Lobry de Bruyn–Van Ekenstein transformation ), or asymmetric transformation (conversion of

147-420: Is favored, or a pre-existing chiral center (which needs not be optically pure) biases the stereochemical outcome during the creation of another. The degree of relative selectivity is measured by the diastereomeric excess . Stereoconvergence can be considered an opposite of stereospecificity, when the reaction of two different stereoisomers yield a single product stereoisomer. The quality of stereoselectivity

168-457: Is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since

189-446: The activation energy difference between the two pathways is finite: both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used. An enantioselective reaction is one in which one enantiomer is formed in preference to the other, in a reaction that creates an optically active product from an achiral starting material, using either

210-516: The (+)-enantiomer also shows moderate affinity for the dizocilpine (MK-801) or phencyclidine (PCP) site of the NMDA receptor (K i = 587 nM in rat brain membranes relative to 45 nM for the σ 1 receptor) and, hence, is an uncompetitive NMDA receptor antagonist as well at higher concentrations. As such, (+)-alazocine is only modestly selective as a ligand of the σ 1 receptor. Both enantiomers of alazocine have very low affinity for

231-416: The NMDA receptor. The sigma σ 2 receptor was discovered and named in 1990, and was identified in part due to the dramatically reduced affinity of alazocine for the receptor relative to the σ 1 receptor (in contrast to non-selective ligands like haloperidol , ditolylguanidine , and (+)-3-PPP , which show similar affinity for both subtypes). Stereoselectivity In chemistry , stereoselectivity

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252-407: The carbocation the substitution can be stereoselective in inter- and intramolecular reactions. In the reaction depicted below the nucleophile (furan) can approach the carbocation formed from the least shielded side away from the bulky t-butyl group resulting in high facial diastereoselectivity: Pinoresinol biosynthesis involved a protein called a dirigent protein . The first dirigent protein

273-418: The major diastereomer resulting from the diastereoselective nucleophilic addition to a carbonyl group next to a chiral center. The chiral center need not be optically pure, as the relative stereochemistry will be the same for both enantiomers. In the example below the (S)-aldehyde reacts with a thiazole to form the (S,S) diastereomer but only a small amount of the (S,R) diastereomer: The Sharpless epoxidation

294-455: The mouse receptor transfected in HEK293 cells). Conversely, the (+)- stereoisomer has little affinity for the opioid receptors (K i for 1,900 nM, 1,600 nM, and 19,000 nM for the μ-, κ-, δ-opioid receptors in guinea pig brain membranes) and instead is a selective and high-affinity agonist of the σ 1 receptor (K i = 48–66 nM in guinea pig brain membranes). However,

315-412: The reactivity of a reaction center elsewhere in the same molecule. A diastereoselective reaction is one in which one diastereomer is formed in preference to another (or in which a subset of all possible diastereomers dominates the product mixture), establishing a preferred relative stereochemistry. In this case, either two or more chiral centers are formed at once such that one relative stereochemistry

336-405: The sigma σ 2 receptor (K i = 13,694 nM and 4,581 nM for the (+)- and (−)-enantiomers, respectively, in rat brain membranes or rat PC12 cells). As such, due to its high affinity for the σ 1 receptor, (+)-alazocine can be used to distinguish between the two sigma receptor subtypes in scientific research, for instance in radioligand binding assays . Taken together, (−)-alazocine

357-539: The κ-opioid receptor (K i = 0.4 nM, EC 50 = 24 nM, and E max = 66% for (±)-alazocine against the mouse receptor transfected in HEK293 cells) and as an antagonist of the μ-opioid receptor (K i = 1.15 nM for (±)-alazocine against the mouse receptor transfected in HEK293 cells). It is also an agonist of the δ-opioid receptor with far lower potency (K i = not reported, IC 50 = 184 nM, and I max = 68% for (±)-alazocine against

378-539: Was discovered in Forsythia intermedia . This protein has been found to direct the stereoselective biosynthesis of (+)- pinoresinol from coniferyl alcohol monomers. Recently, a second, enantiocomplementary dirigent protein was identified in Arabidopsis thaliana , which directs enantioselective synthesis of (−)-pinoresinol. [REDACTED] Haloperidol Too Many Requests If you report this error to

399-420: Was initially thought to be an opioid receptor, and then was confused with the NMDA receptor for a time, but was ultimately distinguished from them both. The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ 1 receptor; subsequent research established that the effects are in fact caused by agonism of the κ-opioid receptor and/or antagonism of

420-428: Was not further developed for clinical use. Subsequently, other benzomorphans, such as pentazocine (an N -dimethylallylbenzomorphan), cyclazocine (an N -cyclopropylmethylbenzomorphan), and phenazocine (an N -phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics. The sigma σ 1 receptor was named in 1976 and (+)-alazocine was described as its prototypical ligand. The receptor

441-417: Was one of the early members of the benzomorphan family of opioid analgesics to be investigated. It was first described in the scientific literature in 1961. Its development resulted from nalorphine (N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s. Alazocine was found to produce strong psychotomimetic effects in humans, and it

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