Reference

Dynamics of aminopyridine block of potassium channels in squid axon membrane

Dynamics of aminopyridine block of potassium channels in squid axon membrane. Yeh, J. Z.; Oxford, G. S.; Wu, C. H.; Narahashi, T. (Med. Cent., Duke Univ., Durham, N. C., USA). J. Gen. Physiol., 68(5), 519-35 (English) 1976. CODEN: JGPLAD. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) 2-Aminopyridine (2-AP)(I) [504-29-0], 3-aminopyridine (3-AP) [462-08-8], and 4-aminopyridine (4-AP) [504-24-5] selectively blocked K channels of squid axon membranes in a manner dependent upon the membrane potential and the duration and frequency of voltage clamp pulses. They were effective when applied to either the internal or the external membrane surface. The steady-state block of K channels by aminopyridines was complete for low depolarizations, and was gradually relieved at higher depolarizations. The K current in the presence of aminopyridines increased more slowly than in control, the change being more conspicuous in 3-AP and 4-AP than in 2-AP. Repetitive pulsing relieved the block in a manner dependent upon the duration and interval of pulses. The recovery from block during a given test pulse was enhanced by increasing the duration of a conditioning depolarizing prepulse. The time const. for this recovery was in the range of 10-20 msec in 3-AP, and shorter in 2-AP. Twin pulse expts.There are some commonly used reagents with their cas registry numbers 504-29-0 and 7440-09-7 in this article. with variable pulse intervals revealed that the time course for re-establishment of block was much shlower in 3-AP and 4-AP than in 2-AP. These results suggest that 2-AP interacts with the K channel more rapidly than 3-AP and 4-AP. The more rapid interaction of 2-AP with K channels was reflected in the kinetics of K current which was faster than that obsd. in 3-AP or 4-AP, and in the pattern of frequency-dependent block which was different from that in 3-AP or 4-AP. The exptl. observations were not satisfactorily described by alterations of Hodgkin-Huxley n-type gating units. Rather, the data are consistent with a simple binding scheme incorporating no changes in gating kinetics which conceives of aminopyridine mol. binding to closed K channels and being released from open channels in a voltage-dependent manner. .

Preparation of N-aminoalkyl amides as agonists of the k opioid receptor useful against gastrointestinal disorders, pain, and pruritus

Dolle, Roland E.; Chu, Guo-Hua; Gu, Minghua (USA ). U.S. Pat. Appl. Publ. US 2005107355 A1 19 May 2005,46 pp. (English). (United States of America). CODEN: USXXCO. CLASS: ICM: A61K031-397. ICS: A61K031-445; A61K031-40; A61K031-165. APPLICATION: US 2003-713746 14 Nov 2003. DOCUMENT TYPE: Patent CA Section: 27 (Heterocyclic Compounds (One Hetero Atom)) Section cross-reference(s): 1, 63 Amide derivs. (shown as I and II; variables defined below; e.g. N-[2-((S)-3-hydroxypyrrolidin-1-yl)-(S)-1-phenylethyl]-N-methyl-2-phenyla minoacetamide (shown as III)) are disclosed. Pharmaceutical compns. contg. these compds., and methods for their use, inter alia, for treating and/or preventing gastrointestinal disorders, pain, and pruritus (no data) are also disclosed. Although the methods of prepn. are not claimed, 36 example prepns. are included. For example, III was prepd. (45 %) by coupling of N-phenylglycine with N-[2-((S)-3-hydroxypyrrolidin-1-yl)-(S)-1-phenylethyl]-N-methylamine dihydrochloride. For I and II: R1 is H or OH; Ra is alkyl; R2 is alkyl, aryl, or aralkyl; R3 is alkyl, or R2 and R3 taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring; R4 is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; Z is -(CH2)oNR5R6 or -(CH2)oC(:O)NR7R8; R5 is H, alkyl, or aryl; R6 is aryl, alkaryl, -CO(NH)pR9, or -SO2R9, provided that at least one of R5 and R6 is other than aryl; R7 is H or alkyl; R8 is alkyl, aryl, aralkyl, alkaryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; R9 is alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; m is the integer 1, 2, or 3; n is the integer 1, 2, or 3; o is the integer 0, 1, 2, or 3; p is the integer 0 or 1; and the quantity (m+n) is an integer 2-5. Compds. in all the examples showed k receptor affinity (K1) <10 mM. For example, III had a Ki = 0.17 nM against the human k receptor with >100′ selectivity vs. the human m and d receptors and was an agonist with an EC50 = 0.05 nM. It exhibited a % A = 96.2% at a dose of 300 mg, i.paw in the in vivo formalin-induced nociception assay. This compd. also blocked the action of HOAc-induced writhing when administered s.c. with an ED50 = 0.017 mg/kg. Keywords aminoalkyl carboxamide prepn kappa opioid receptor agonist therapeutic use nitrogen heterocycle aminoalkyl carboxamide prepn kappa opioid receptor agonist Index Entries Amides, preparation N-aminoalkyl, drug candidate; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy allergic dermatitis; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Dermatitis allergic; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy atopy; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Edema cerebral; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Dermatitis contact; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Anesthetics Anti-inflammatory agents Antibacterial agents Antiviral agents Fungicides Opioids drug candidates and codrugs; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Brain, disease edema; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Intestine, disease ileus; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Skin, disease insect bite; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Blood-brain barrier not crossed by drug candidates; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy inhibitors Analgesics Antitussives Combination chemotherapy Cough Digestive tract, disease Diuretics Drug delivery systems Eczema Human Pain Pruritus Psoriasis prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Opioid receptors k-opioid, in central nervous system, agonists; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 57-27-2, biological studies 57-42-1 76-41-5 76-42-6 76-57-3 76-99-3 77-07-6 125-28-0 125-29-1 359-83-1 437-38-7 466-99-9 469-62-5 15686-91-6 20594-83-6 27203-92-5 42408-82-2 52485-79-7 53648-55-8 56030-54-7 71195-58-9 codrug; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 851679-94-2 851679-95-3 851679-96-4 851679-98-6 851679-99-7 851680-00-7 851680-01-8 851680-03-0 851680-08-5 851680-15-4 851680-16-5 851680-17-6 851680-19-8 851680-20-1 851680-21-2 851680-22-3 851680-26-7 851680-28-9 851680-29-0 851680-30-3 851680-31-4 851680-34-7 851680-38-1 851680-40-5 851680-43-8 851680-46-1 851680-47-2 851680-48-3 851680-51-8 851680-52-9 851680-53-0 851680-54-1 851680-55-2 851680-57-4 851680-58-5 851680-59-6 851680-60-9 drug candidate; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 62-53-3, reactions 96-50-4 100-01-6, reactions 100-46-9, reactions 103-01-5 103-71-9, reactions 108-30-5, reactions 109-83-1 123-75-1, reactions 462-08-8 873-74-5 1694-92-4 1885-29-6 2237-30-1 2445-85-4 3153-37-5 5680-79-5 10147-36-1 14108-81-7 32807-28-6 37517-81-0 40204-26-0 53990-33-3 64377-71-5 91192-27-7 136780-20-6 142773-73-7 171056-73-8 207847-96-9 672951-66-5 102-14-7 103-40-2 579-98-6 619-91-0 2327-84-6 3016-39-5 5430-83-1 15580-32-2 19692-00-3 20059-60-3 21911-75-1 23284-84-6 25604-13-1 42288-26-6 58199-15-8 66825-16-9 67045-01-6 69479-87-4 76311-94-9 77311-21-8 78096-15-8 90544-88-0 104892-36-6 152085-47-7 163460-75-1 325168-04-5 327069-81-8 328011-26-3 329205-47-2 591234-88-7 773844-67-0 851679-97-5 851680-04-1 851680-10-9 851680-12-1 851680-13-2 851680-14-3 851680-18-7 851680-23-4 851680-24-5 851680-25-6 851680-27-8 851680-32-5 851680-33-6 851680-35-8 851680-36-9 851680-37-0 851680-39-2 851680-41-6 851680-42-7 851680-44-9 851680-45-0 851680-49-4 851680-50-7 851680-56-3 prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus