Alvimopan (also known as ADL 8-2698; LY 246736; HSDB-7704) is a novel peripheral micro opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. Alvimopan acts for a longer period of time than other antagonists that act more quickly, which may be connected to a slower rate of dissociation from the micro opioid receptor. In comparison to the long-acting partial agonist buprenorphine (t(1/2)=44 min), alvimopan's dissociation rate from the micro opioid receptor (t(1/2)=30–44 min) was slower than that of the antagonists naloxone (t(1/2)=0.82 min) and N-methylnaltrexone (t(1/2)=0.46 min). Moreover, after preincubation with the micro opioid receptor, increases were seen in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone or methylnaltrexone. Alvimopan has a slower rate of dissociation from the micro opioid receptor than other antagonists with shorter half-lives, which is consistent with its prolonged duration of action. It may also have greater potency if given before exogenous opioid dosing.

Physicochemical Properties

Molecular Formula	C25H36N2O6
Molecular Weight	460.57
Exact Mass	460.257
Elemental Analysis	C, 65.20; H, 7.88; N, 6.08; O, 20.84
CAS #	170098-38-1
Related CAS #	Alvimopan; 156053-89-3; Alvimopan monohydrate; 1383577-62-5
PubChem CID	5488547
Appearance	White to off-white solid powder
Density	1.166g/cm3
Boiling Point	684.1ºC at 760mmHg
Melting Point	210-213ºC
Flash Point	367.5ºC
Vapour Pressure	1.18E-19mmHg at 25°C
Index of Refraction	1.572
LogP	3.251
Hydrogen Bond Donor Count	5
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	8
Heavy Atom Count	33
Complexity	606
Defined Atom Stereocenter Count	3
SMILES	O([H])C1=C([H])C([H])=C([H])C(=C1[H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])N(C([H])([H])[C@@]([H])(C(N([H])C([H])([H])C(=O)O[H])=O)C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])[C@]1([H])C([H])([H])[H].O([H])[H].O([H])[H]
InChi Key	USPVLEIQIUNQGE-DBFLIVQGSA-N
InChi Code	InChI=1S/C25H32N2O4.2H2O/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19;;/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30);2*1H2/t18-,20-,25+;;/m0../s1
Chemical Name	2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl]amino]acetic acid;dihydrate
Synonyms	LY246736 dihydrate; LY246736; LY-246736; HSDB 7704; HSDB7704 dihydrate; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698 dihydrate; Alvimopan dihydrate. Brand name: Entereg.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	μ-opioid receptor ( Ki = 0.77 nM ); δ-opioid receptor ( Ki = 4.4 nM ); κ-opioid receptor ( Ki = 40 nM )
ln Vitro	In vitro activity: Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Upon testing at various non-opioid receptors, ion channels, and enzymes, alvimopan (1 or 10 μM) does not exhibit any noteworthy affinity[2].
ln Vivo	Alvimopan only counteracts morphine-induced analgesia in animals at relatively high dosages; in order for the drug to cross the blood-brain barrier, very high plasma concentrations are required. Alvimopan is about 200 times more effective at blocking peripheral than central μ-receptors after intravenous injection. Alvimopan is also very active when taken orally. Alvimopan administered intravenously to dogs increased plasma area under the concentration-time curve and peak plasma concentrations in a dose-dependent manner. Oral doses up to 100 mg/kg, however, resulted in low plasma concentrations (mean Cmax = 92.9 ng/ml) due to poor systemic absorption, which led to an oral bioavailability of about 0.03%. In dogs and rabbits, the half-life of alvimopan is thought to be roughly 10 minutes following intravenous administration[1].
Enzyme Assay	Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Tested at both 1 and 10 μM, alvimopan does not exhibit any noteworthy affinity for a wide variety of non-opioid receptors, ion channels, or enzymes.
Animal Protocol	100 mg/kg; i.v. dogs and rabbits
References	[1]. P T. 2008 Oct; 33(10): 574, 580-583. [2]. Therapeutics. 2009, 1: 199-213.
Additional Infomation	Alvimopan is a synthetic trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine with peripherally selective opioid mu receptor antagonist activity. Alvimopan is a selective and competitive antagonist at mu-opioid receptors, found in myenteric and submucosal neurons and the immune cells of the lamina propria in the human gut. Upon administration, this agent binds to mu-opioid receptors in the gut, thereby reversing opioid-related disturbances in gut motility. Alvimopan is approximately three to nine times more potent than naloxone. See also: Alvimopan (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO: 33.3~92 mg/mL (72.4~199.8 mM) Water: >1mg/mL Ethanol: >1mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1712 mL	10.8561 mL	21.7122 mL
	5 mM	0.4342 mL	2.1712 mL	4.3424 mL
	10 mM	0.2171 mL	1.0856 mL	2.1712 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.