Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist.
Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.
Altenbach
Robert J
RJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA. Robert.j.altenbach@abbott.com
Khilevich
Albert
A
Kolasa
Teodozyj
T
Rohde
Jeffrey J
JJ
Bhatia
Pramila A
PA
Patel
Meena V
MV
Searle
Xenia B
XB
Yang
Fan
F
Bunnelle
William H
WH
Tietje
Karin
K
Bayburt
Erol K
EK
Carroll
William A
WA
Meyer
Michael D
MD
Henry
Rodger
R
Buckner
Steven A
SA
Kuk
Jane
J
Daza
Anthony V
AV
Milicic
Ivan V
IV
Cain
John C
JC
Kang
Chae H
CH
Ireland
Lynne M
LM
Carr
Tracy L
TL
Miller
Thomas R
TR
Hancock
Arthur A
AA
Nakane
Masaki
M
Esbenshade
Timothy A
TA
Brune
Michael E
ME
O'Neill
Alyssa B
AB
Gauvin
Donna M
DM
Katwala
Sweta P
SP
Holladay
Mark W
MW
Brioni
Jorge D
JD
Sullivan
James P
JP
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; C547721:Adra1d protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D007093:Imidazoles; C445279:N-(5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl)methanesulfonamide; D009281:Naphthalenes; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes